Substituted p-diaminobenzene derivatives

ABSTRACT

The present invention relates to aniline derivatives of the general formula I or pharmaceutically acceptable salts thereof and their use.

This application is a §371 national stage of International ApplicationNo. PCT/DK2004/000186, filed Mar. 18, 2004, which was published inEnglish as International Publication No. WO 2004/082677, and claims thebenefit of priority of U.S. Provisional Application No. 60/456,698,filed Mar. 21, 2003 and Danish Patent Application No. PA 200300441,filed Mar. 21, 2003.

FIELD OF THE INVENTION

The present invention relates to novel substituted p-diaminobenzenederivatives being openers of the KCNQ family potassium ion channels. Thecompounds are useful for the prevention, treatment and inhibition ofdisorders and diseases being responsive to opening of the KCNQ familypotassium ion channels, one such disease is epilepsy.

BACKGROUND OF THE INVENTION

Ion channels are cellular proteins that regulate the flow of ions,including potassium, calcium, chloride and sodium into and out of cells.Such channels are present in all animal and human cells and affect avariety of processes including neuronal transmission, musclecontraction, and cellular secretion.

Humans have over 70 genes encoding potassium channel subunits (JentschNature Reviews Neuroscience 2000, 1, 21-30) with a great diversity withregard to both structure and function. Neuronal potassium channels,which are found in the brain, are primarily responsible for maintaininga negative resting membrane potential, as well as controlling membranerepolarisation following an action potential.

One subset of potassium channel genes is the KCNQ family. Mutations infour out of five KCNQ genes have been shown to underlie diseasesincluding cardiac arrhythmias, deafness and epilepsy (Jentsch NatureReviews Neuroscience 2000, 1, 21-30).

The KCNQ4 gene is thought to encode the molecular correlate of potassiumchannels found in outer hair cells of the cochlea and in Type I haircells of the vestibular apparatus, in which mutations can lead to a formof inherited deafness.

KCNQ1 (KvLQT1) is co-assembled with the product of the KCNE1 (minimalK(+)-channel protein) gene in the heart to form a cardiac-delayedrectifier-like K(+) current. Mutations in this channel can cause oneform of inherited long QT syndrome type 1 (LQT1), as well as beingassociated with a form of deafness (Robbins Pharmacol Ther 2001, 90,1-19).

The genes KCNQ2 and KCNQ3 were discovered in 1988 and appear to bemutated in an inherited form of epilepsy known as benign familialneonatal convulsions (Rogawski Trends in Neurosciences 2000, 23,393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes arelocalised in the pyramidal neurons of the human cortex and hippocampus,regions of the brain associated with seizure generation and propagation(Cooper et al. Proceedings National Academy of Science USA 2000, 97,4914-4919).

KCNQ2 and KCNQ3 are two potassium channel subunits that form“M-currents” when expressed in vitro. The M-current is anon-inactivating potassium current found in many neuronal cell types. Ineach cell type, it is dominant in controlling membrane excitability bybeing the only sustained current in the range of action potentialinitiation (Marrion Annual Review Physiology 1997, 59, 483-504).Modulation of the M-current has dramatic effects on neuronalexcitability, for example activation of the current will reduce neuronalexcitability. Openers of these KCNQ channels, or activators of theM-current, will reduce excessive neuronal activity and may thus be ofuse in the treatment, prevention or inhibition of seizures and otherdiseases and disorders characterised by excessive neuronal activity,such as neuronal hyperexcitability including convulsive disorders,epilepsy and neuropathic pain.

Retigabine (D-23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamicacid ethyl ester) and analogues thereof are disclosed in EP554543.Retigabine is an anti-convulsive compound with a broad spectrum andpotent anticonvulsant properties, both in vitro and in vivo. It isactive after oral and intraperitoneal administration in rats and mice ina range of anticonvulsant tests including: electrically inducedseizures, seizures induced chemically by pentylenetetrazole, picrotoxinand N-methyl-D-aspartate (NMDA) and in a genetic animal model, the DBA/2mouse (Rostock et al. Epilepsy Research 1996, 23, 211-223). In addition,retigabine is active in the amygdala kindling model of complex partialseizures, further indicating that this compound has potential foranti-convulsive therapy. In clinical trials, retigabine has recentlyshown effectiveness in reducing the incidence of seizures in epilepticpatients (Bialer et al. Epilepsy Research 2002, 51, 31-71).

Retigabine has been shown to activate a K(+) current in neuronal cellsand the pharmacology of this induced current displays concordance withthe published pharmacology of the M-channel, which recently wascorrelated to the KCNQ2/3 K(+) channel heteromultimer. This suggeststhat activation of KCNQ2/3 channels may be responsible for some of theanticonvulsant activity of this agent (Wickenden et al. MolecularPharmacology 2000, 58, 591-600)—and that other agents working by thesame mechanism may have similar uses.

KCNQ 2 and 3 channels have also been reported to be upregulated inmodels of neuropathic pain (Wickenden et al. Society for NeuroscienceAbstracts 2002, 454.7), and potassium channel modulators have beenhypothesised to be active in both neuropathic pain and epilepsy(Schroder et al. Neuropharmacology 2001, 40, 888-898).

Retigabine has also been shown to be beneficial in animal models ofneuropathic pain (Blackburn-Munro and Jensen European Journal ofPharmacology 2003, 460, 109-116), and it is thus suggested that openersof KCNQ channels will be of use in treating pain disorders includingneuropathic pain.

The localisation of KCNQ channel mRNA is reported in brain and othercentral nervous system areas associated with pain (Goldstein et al.Society for Neuroscience Abstracts 2003, 53.8).

In addition to a role in neuropathic pain, the expression of mRNA forKCNQ 2-5 in the trigeminal and dorsal root ganglia and in the trigeminalnucleus caudalis implies that openers of these channels may also affectthe sensory processing of migraine pain (Goldstein et al. Society forNeuroscience Abstracts 2003, 53.8).

Recent reports demonstrate that mRNA for KCNQ 3 and 5, in addition tothat for KCNQ2, are expressed in astrocytes and glial cells. Thus KCNQ2, 3 and 5 channels may help modulate synaptic activity in the CNS andcontribute to the neuroprotective effects of KCNQ channel openers (Nodaet al., Society for Neuroscience Abstracts 2003, 53.9).

Retigabine and other KCNQ modulators may thus exhibit protection againstthe neurodegenerative aspects of epilepsy, as retigabine has been shownto prevent limbic neurodegeneration and the expression of markers ofapoptosis following kainic acid-induced status epilepticus in the rat(Ebert et al. Epilepsia 2002, 43 Suppl 5, 86-95). This may haverelevance for preventing the progression of epilepsy in patients, i.e.be anti-epileptogenic. Retigabine has also been shown to delay theprogression of hippocampal kindling in the rat, a further model ofepilepsy development (Tober et al. European Journal Of Pharmacology1996, 303, 163-169).

It is thus suggested that these properties of retigabine and other KCNQmodulators may prevent neuronal damage induced by excessive neuronalactivation, and may be of use in the treatment of neurodegenerativediseases, and be disease modifying (or anti-epileptogenic) in patientswith epilepsy.

Given that anticonvulsant compounds such as benzodiazepines andchlormethiazole are used clincially in the treatment of the ethanolwithdrawal syndrome and that other anticonvulsant compounds e.g.gabapentin, are very effective in animal models of this syndrome (Watsonet al. Neuropharmacology 1997, 36, 1369-1375), other anticonvulsantcompounds such as KCNQ openers are thus expected to be effective in thiscondition.

mRNA for KCNQ 2 and 3 subunits are found in brain regions associatedwith anxiety and emotional behaviours such as bipolar disorder e.g.hippocampus and amygdala (Saganich et al. Journal of Neuroscience 2001,21, 4609-4624), and retigabine is reportedly active in some animalmodels of anxiety-like behaviour (Hartz et al. Journal ofPsychopharmacology 2003, 17 suppl 3, A28,B16), and other clinically usedanticonvulsant compounds are used in the treatment of bipolar disorder.

WO 200196540 discloses the use of modulators of the M-current formed byexpression of KCNQ2 and KCNQ3 genes for insomnia, while WO 2001092526discloses that modulators of KCNQ5 can be utilized for the treatment ofsleep disorders.

WO01/022953 describes the use of retigabine for prophylaxis andtreatment of neuropathic pain such as allodynia, hyperalgesic pain,phantom pain, neuropathic pain related to diabetic neuropathy andneuropathic pain related to migraine.

WO02/049628 describes the use of retigabine for the prevention,treatment, inhibition and amelioration of anxiety disorders such asanxiety, generalized anxiety disorder, panic anxiety, obsessivecompulsive disorder, social phobia, performance anxiety, post-traumaticstress disorder, acute stress reaction, adjustment disorders,hypochondriacal disorders, separation anxiety disorder, agoraphobia andspecific phobias.

WO97/15300 describes the use of retigabine for the treatment ofneurodegenerative disorders such as Alzheimer's disease; Huntington'schorea; sclerosis such as multiple sclerosis and amyotrophic lateralsclerosis; Creutzfeld-Jakob disease; Parkinson's disease;encephalopathies induced by AIDS or infection by rubella viruses, herpesviruses, borrelia and unknown pathogens; trauma-inducedneurodegenerations; neuronal hyperexcitation states such as inmedicament withdrawal or intoxication; and neurodegenerative diseases ofthe peripheral nervous system such as polyneuropathies andpolyneuritides.

Hence, there is a great desire for novel compounds, which are potentopeners of the KCNQ family potassium channels.

Also desired are novel compounds with improved properties relative toknown compounds, which are openers of the KCNQ family potassiumchannels, such as retigabine. Improvement of one or more of thefollowing parameters is desired: half-life, clearance, selectivity,interactions with other medications, bioavailability, potency,formulability, chemical stability, metabolic stability, membranepermeability, solubility and therapeutic index. The improvement of suchparameters may lead to improvements such as:

-   -   an improved dosing regime by reducing the number of required        doses a day,    -   ease of administration to patients on multiple medications,    -   reduced side effects,    -   enlarged therapeutic index,    -   improved tolerability or    -   improved compliance.

SUMMARY OF THE INVENTION

One object of the present invention is to provide novel compounds, whichare potent openers of the KCNQ family potassium channels.

The compounds of the invention are substituted aniline derivatives ofthe general formula I or salts thereof

wherein Y, U, X, Z, s, q, R¹, R² and R³ are as defined below.

The invention further relates to a pharmaceutical composition comprisingone or more compounds of formula I and the use thereof.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to substitutedp-diaminobenzene derivatives of the general formula I

wherein

-   s is 0 or 1;-   U is O, S, SO₂, SO₂NR¹¹, CO—O or CO—NR¹¹; wherein-   R¹¹ is selected from the group consisting of hydrogen,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; or-   R² and R¹¹ together with the nitrogen atom form a 5-8 membered    saturated or unsaturated ring which optionally contains 1, 2 or 3    further heteroatoms;-   q is 0 or 1;-   X is CO or SO₂; with the proviso that q is 0 when X is SO₂;-   Z is O or S;-   R¹ is selected from the group consisting of hydrogen,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, acyl,    hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano-C₁₋₆-alk(en/yn)yl,    cyano-C₃₋₈-cycloalk(en)yl and    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl;-   R² is selected from the group consisting of hydrogen,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,    Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    acyl, hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, halogen,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano,    cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl,    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    NR¹⁰R^(10′)—C₁₋₆-alk(en/yn)yl, NR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl and    NR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; wherein-   R¹⁰ and R^(10′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, hydroxy-C₁₋₆-alk(en/yn)yl,    hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano-C₁₋₆-alk(en/yn)yl,    cyano-C₃₋₈-cycloalk(en)yl and    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, or-   R¹⁰ and R^(10′) together with the nitrogen atom form a 5-8 membered    saturated or unsaturated ring which optionally contains 1, 2 or 3    further heteroatoms;-   provided that when R² is halogen or cyano then s is 0; and-   provided that U is O or S when s is 1 and R² is a hydrogen atom or    acyl;-   R³ is selected from the group consisting of C₁₋₆-alk(en/yn)yl,    C₃₋₈-cycloalk(en)yl, heterocycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,    heterocycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,    Ar—C₃₋₈-cycloalk(en)yl, Ar-heterocycloalk(en)yl,    Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    Ar—C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    Ar—C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,    C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,    C₃₋₈-cycloalk(en)yloxy-C₁₋₆-alk(en/yn)yl,    C₁₋₆-alk(en/yn)yloxy-C₃₋₈-cycloalk(en)yl,    C₁₋₆-alk(en/yn)yloxy-heterocycloalk(en)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,    Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,    C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,    C₃₋₈-cycloalk(en)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,    hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-heterocycloalk(en)yl, hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆    alk(en/yn)yl, hydroxy-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    hydroxy-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-heterocycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    halo-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,    halo-C₁₋₆-alk(en/yn)yl-Ar, halo-C₃₋₈-cycloalk(en)yl-Ar,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl-Ar,    halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl-Ar,    cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl,    cyano-heterocycloalk(en)yl, cyano-C₃₋₈    cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    cyano-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    cyano-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,    acyl-C₁₋₆-alk(en/yn)yl, acyl-C₃₋₈-cycloalk(en)yl,    acyl-heterocycloalk(en)yl,    acyl-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    acyl-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    acyl-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, NR¹²R^(12′), optionally    substituted NR¹²R^(12′)—C₁₋₆-alk(en/yn)yl, optionally substituted    NR¹²R^(12′)—C₃₋₈-cycloalk(en)yl, optionally substituted    NR¹²R^(12′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; wherein-   R¹² and R^(12′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,    Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    Ar-heterocycloalk(en)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,    Ar-oxy-C₃₋₈-cycloalk(en)yl,    Ar-oxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    Ar-oxy-heterocycloalk(en)yl, hydroxy-C₁₋₆-alk(en/yn)yl,    hydroxy-C₃₋₈-cycloalk(en)yl, hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆    alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₃₋₈-alk(en/yn)yl, Cyano-C₁₋₆-alk(en/yn)yl,    cyano-C₃₋₈-cycloalk(en)yl and    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, or-   R¹² and R^(12′) together with the nitrogen atom form a 5-8 membered    saturated or unsaturated ring which optionally contains 1, 2 or 3    further heteroatoms;    with the proviso that when R³ is NR¹²R^(12′) then q is 0; and-   Y represents a group of formula XXIV, XXV, XXVI, XXVII, XXVIII,    XXXXI or XXXXII:

wherein

-   the line represents a bond attaching the group represented by Y to    the carbon atom;-   W is O or S;-   V is N, C or CH;-   T is N, NH or O,-   a is 0, 1, 2 or 3;-   b is 0, 1, 2, 3 or 4;-   c is 0 or 1;-   d is 0, 1, 2 or 3;-   e is 0, 1 or 2;-   f is 0, 1, 2, 3, 4 or 5;-   g is 0, 1, 2, 3 or 4;-   h is 0, 1, 2 or 3;-   j is 0, 1 or 2;-   k is 0, 1, 2 or 3; and-   each R⁵ is independently selected from the group consisting of a    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,    Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    Ar-oxy, Ar-oxy-C₁₋₆-alk(en/yn)yl, Ar-oxy-C₃₋₈-cycloalk(en)yl,    C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,    Ar-oxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, acyl,    C₁₋₆-alk(en/yn)yloxy, C₃₋₈-cycloalk(en)yloxy,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn) yloxy,    C₁₋₆-alk(en/yn)yloxy-carbonyl, halogen, halo-C₁₋₆-alk(en/yn)yl,    halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, —CO—NR⁶R^(6′), cyano,    cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl,    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, NR⁷R^(7′), S—R⁸ and    SO₂R⁸, or-   two adjacent R⁵ together with the aromatic group form a 5-8 membered    ring which optionally contains one or two heteroatoms;-   R⁶ and R^(6′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl and Ar;-   R⁷ and R^(7′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar,    heterocycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    heterocycloalk(en)yl-C₃₋₈-cycloalk(en)yl,    heterocycloalk(en)yl-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    heterocycloalk(en)yl-Ar and acyl; or-   R⁷ and R^(7′) together with the nitrogen atom form a 5-8 membered    saturated or unsaturated ring which optionally contains 1, 2 or 3    further heteroatoms; and-   R⁸ is selected from the group consisting of hydrogen,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar and —NR⁹R^(9′); wherein-   R⁹ and R^(9′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl and    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl;    or salts thereof.

In one embodiment, the invention relates to compounds of formula I,wherein s is 1.

In another embodiment, the invention relates to compounds of formula I,wherein s is 0.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1 and U is O.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1 and U is S.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1 and U is SO₂.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1 and U is SO₂NR¹¹. In such compounds, the sulphur atomof SO₂NR¹¹ is attached to the benzene ring of formula I whereas thenitrogen atom is attached to R².

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1 and U is CO—O. In such compounds, the carbonyl groupof CO—O is attached to the benzene ring of formula I whereas the oxygenatom is attached to R².

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1 and U is CO—NR¹¹. In such compounds, the carbonylgroup of CO—NR¹¹ is attached to the benzene ring of formula I whereasthe nitrogen atom is attached to R².

In yet another embodiment, the invention relates to compounds of formulaI, wherein R¹¹ is a hydrogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is SO₂, with the proviso that q is 0 when X is SO₂.

In yet another embodiment, the invention relates to compounds of formulaI, wherein q is 0.

In yet another embodiment, the invention relates to compounds of formulaI, wherein q is 1.

In yet another embodiment, the invention relates to compounds of formulaI, wherein q is 1 and Z is O.

In yet another embodiment, the invention relates to compounds of formulaI, wherein q is 1 and Z is S.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 1 and Z is O.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 1 and Z is S.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO and q is 0.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is SO₂ and q is 0.

In another embodiment, the invention relates to compounds of formula I,wherein R¹ is selected from the group consisting of acyl,hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk(en)yl,hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₃₋₈-cycloalk(en)yl, halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl andcyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

One embodiment of the invention relates to compounds of the generalformula I, wherein R¹ is selected from the group consisting of hydrogen,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl andC₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

A preferred embodiment of the invention relates to compounds of thegeneral formula I, wherein R¹ is selected from the group consisting ofhydrogen and C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R¹ is C₁₋₆-alk(en/yn)yl, typically C₁₋₃-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R¹ is a hydrogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is selected from the group consisting of hydrogen, acyl,hydroxy-C₁₋₆-alk(en/yn)yl,hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano-C₁₋₆-alk(en/yn)yl,cyano-C₃₋₈-cycloalk(en)yl, cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,NR¹⁰R^(10′)—C₁₋₆-alk(en/yn)yl, NR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl andNR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; wherein

-   R¹⁰ and R^(10′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, hydroxy-C₁₋₆-alk(en/yn)yl,    hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano-C₁₋₆-alk(en/yn)yl,    cyano-C₃₋₈-cycloalk(en)yl and    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, or-   R¹⁰ and R^(10′) together with the nitrogen atom form a 5-8 membered    saturated or unsaturated ring which optionally contains 1, 2 or 3    further heteroatoms;    provided that U is O or S when s is 1 and R² is a hydrogen atom or    acyl.

When R² represents NR¹⁰R^(10′)—C₁₋₆-alk(en/yn)yl,NR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl orNR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl then the nitrogen atomis linked to the remainder of the molecule via C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl or C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is selected from the group consisting of hydrogen,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,halogen, halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl and cyano;

-   provided that when R² is halogen or cyano then s is 0; and-   provided that U is O or S when s is 1 and R² is a hydrogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is selected from the group consisting of hydrogen,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,halogen, halo-C₁₋₆-alk(en/yn)yl and cyano;

-   provided that when R² is halogen or cyano then s is 0; and-   provided that U is O or S when s is 1 and R² is a hydrogen atom.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein R² is selected from the group consisting ofC₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, Ar—C₁₋₆-alk(en/yn)yl, halogenand cyano;

-   provided that when R² is halogen or cyano then s is 0.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is a hydrogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is not a hydrogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is C₁₋₆-alk(en/yn)yl, C₁₋₃-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is C₃₋₈-cycloalk(en)yl, typically C₃₋₆-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is not Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is Ar—C₁₋₆-alk(en/yn)yl, typically Ar—C₁₋₃-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is a halogen atom, typically a chloro atom, a bromo atomor an iodo atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is halo-C₁₋₆-alk(en/yn)yl, typicallyhalo-C₁₋₃-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is not halo-C₁₋₆-alk(en/yn)yl, typicallyhalo-C₁₋₃-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R² is cyano.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R¹⁰ and R^(10′) are independently selected from the groupconsisting of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R¹⁰ and R^(10′) are independently selected from the groupconsisting of hydrogen and C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is O and R² is selected from the group consistingof C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar—C₁₋₆-alk(en/yn)yl,Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl andhalo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is O and R² is selected from the group consistingof C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, Ar—C₁₋₆-alk(en/yn)yl andhalo-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is O and R² is selected from the group consistingof C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl and Ar—C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is S and R² is selected from the group consistingof C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar—C₁₋₆-alk(en/yn)yl, Ar—C₃₋₈cycloalk(en)yl and Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆ alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is S and R² is selected from the group consistingof C₁₋₆-alk(en/yn)yl and Ar—C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is S and R² is selected from the group consistingof C₃₋₈-cycloalk(en)yl and Ar—C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 0 and R² is selected from the group consisting ofC₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, halogen,halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl and cyano.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 0 and R² is selected from the group consisting ofC₁₋₆-alk(en/yn)yl, Ar, halogen, halo-C₁₋₆-alk(en/yn)yl and cyano.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 0 and R² is selected from the group consisting ofC₁₋₆-alk(en/yn)yl, halogen and cyano.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is CO—O and R² is selected from the groupconsisting of C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is CO—O and R² is C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is CO—NR¹¹, R¹¹ is a hydrogen atom and R² isdifferent from C₃₋₈-cycloalk(en)yl, hydroxy-C₃₋₈-cycloalk(en)yl,halo-C₃₋₈-cycloalk(en)yl, cyano-C₃₋₈-cycloalk(en)yl and Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is CO—NR¹¹ and R² is selected from the groupconsisting of C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is CO—NR¹¹ and R² is C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R¹¹ is a hydrogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is selected from the group consisting ofheterocycloalk(en)yl, C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,Ar-heterocycloalk(en)yl, Ar—C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,C₁₋₆-alk(en/yn)yloxy-heterocycloalk(en)yl, hydroxy-C₁₋₆-alk(en/yn)yl,hydroxy-C₃₋₈-cycloalk(en)yl, hydroxy-heterocycloalk(en)yl,hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,hydroxy-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,hydroxy-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,halo-heterocycloalk(en)yl, halo-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl,cyano-heterocycloalk(en)yl, cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,cyano-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,cyano-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, acyl-C₁₋₆-alk(en/yn)yl,acyl-C₃₋₈-cycloalk(en)yl, acyl-heterocycloalk(en)yl,acyl-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,acyl-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,acyl-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, NR¹²R^(12′); wherein

-   R¹² and R^(12′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,    Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    Ar-heterocycloalk(en)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,    Ar-oxy-C₃₋₈-cycloalk(en)yl,    Ar-oxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    Ar-oxy-heterocycloalk(en)yl, hydroxy-C₁₋₆-alk(en/yn)yl,    hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano-C₁₋₆-alk(en/yn)yl,    cyano-C₃₋₈-cycloalk(en)yl and    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, or-   R¹² and R^(2′) together with the nitrogen atom form a 5-8 membered    saturated or unsaturated ring which optionally contains 1, 2 or 3    further heteroatoms;    with the proviso that when R³ is NR¹²R^(12′) then q is 0.

When R³ represents NR¹²R^(12′)—C₁₋₆-alk(en/yn)yl,NR¹²R^(12′)—C₃₋₈-cycloalk(en)yl orNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl then the nitrogen atomis linked to the X-(Z)_(p) group via the C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl or C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl group.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is selected from the group consisting ofC₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,heterocycloalk(en)yl-C₁₋₆-alk(en/yn)yl, heterocycloalk(en)yl, Ar,Ar—C₁₋₆-alk(en/yn)yl, Ar—C₃₋₈-cycloalk(en)yl,Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,Ar—C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yloxy-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-C₃₋₈-cycloalk(en)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl, halo-C₁₋₆-alk(en/yn)yl-Ar,halo-C₃₋₈-cycloalk(en)yl-Ar,halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl-Ar,halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl-Ar, NR¹²R¹²′, optionallysubstituted NR¹²R^(12′)—C₁₋₆-alk(en/yn)yl, optionally substitutedNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl and optionally substitutedNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is selected from the group consisting ofC₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,heterocycloalk(en)yl-C₁₋₆-alk(en/yn)yl, heterocycloalk(en)yl, Ar,Ar—C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,Ar-oxy-C₁₋₆-alk(en/yn)yl, Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl-Ar, NR¹²R^(12′), optionally substitutedNR¹²R^(12′)—C₁₋₆-alk(en/yn)yl, and optionally substitutedNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein R³ is C₁₋₆-alk(en/yn)yl, typically C₁₋₃-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is heterocycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is not heterocycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is heterocycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is not heterocycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is Ar—C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is not C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is Ar-oxy-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is halo-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is halo-C₁₋₆-alk(en/yn)yl-Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is not halo-C₁₋₆-alk(en/yn)yl-Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is NR¹²R^(12′).

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is not NR¹²R^(12′).

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is optionally substituted NR¹²R^(12′)—C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is different from optionally substitutedNR¹²R^(12′)—C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is optionally substituted NR¹²R^(12′)—C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is different from optionally substitutedNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is optionally substitutedNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R³ is different from optionally substitutedNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R¹² and R^(12′) are independently selected from the groupconsisting of Ar-heterocycloalk(en)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,Ar-oxy-C₃₋₈-cycloalk(en)yl,Ar-oxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,Ar-oxy-heterocycloalk(en)yl, hydroxy-C₁₋₆-alk(en/yn)yl,hydroxy-C₃₋₈-cycloalk(en)yl,hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₃₋₈-cycloalk(en)yl, halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,cyano-C₁₋₆-alk(en/Yn)yl, cyano-C₃₋₈-cycloalk(en)yl andcyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, or

-   R¹² and R^(12′) together with the nitrogen atom form a 5-8 membered    saturated or unsaturated ring which optionally contains 1, 2 or 3    further heteroatoms;    with the proviso that when R³ is NR¹²R^(12′) then q is 0.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R¹² and R^(12′) are independently selected from the groupconsisting of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R¹² and R^(12′) are independently selected from the groupconsisting of hydrogen, C₁₋₆-alk(en/yn)yl and Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein at least one of R¹² and R^(12′) is a hydrogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein at least one of R¹² and R^(12′) is C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein at least one of R¹² and R^(12′) is Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 1, Z is O and R³ is selected from the groupconsisting of C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl, Ar, Ar—C₃₋₈ alk(en/yn)yl,Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,Ar—C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yloxy-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-C₃₋₈-cycloalk(en)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₃₋₈-cycloalk(en)yl, halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl andhalo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 1, Z is O and R³ is selected from the groupconsisting of C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl and halo-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 1, Z is O and R³ is notC₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 1, Z is O and R³ is C₁₋₆-alk(en/yn)yl,typically C₁₋₃-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 1, Z is S and R³ is selected from the groupconsisting of C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl, Ar—C₁₋₆-alk(en/yn)yl,Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl andAr—C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 1, Z is S and R³ is selected from the groupconsisting of C₁₋₆-alk(en/yn)yl and Ar—C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 1, Z is S and R³ is C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 0, R³ is selected from the group consisting ofC₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl, heterocycloalk(en)yl, Ar,Ar—C₁₋₆-alk(en/yn)yl, Ar—C₃₋₈-cycloalk(en)yl,Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar—C₁₋₆alk(en/yn)yl-C₃₋₈-cycloalk(en)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl, halo-C₁₋₆-alk(en/yn)yl-Ar,halo-C₃₋₈-cycloalk(en)yl-Ar,halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl-Ar,halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl-Ar, NR¹²R^(12′), optionallysubstituted NR¹²R^(12′)—C₁₋₆-alk(en/yn)yl, and optionally substitutedNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 0, R³ is selected from the group consisting ofC₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, heterocycloalk(en)yl, Ar,Ar—C₁₋₆-alk(en/yn)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl-Ar, NR¹²R^(12′), optionally substitutedNR¹²R^(12′)—C₁₋₆-alk(en/yn)yl, and optionally substitutedNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is SO₂, q is 0 and R³ is selected from the group consistingof C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl, Ar—C₁₋₆-alk(en/yn)yl,Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,Ar—C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is SO₂, q is 0 and R³ is selected from the group consistingof C₁₋₆-alk(en/yn)yl and Ar—C₁₋₆-alk(en/yn)yl.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein R³ is Ar and q is 1.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein R³ is Ar and q is 0.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein R³ is not Ar when q is 0.

In another embodiment, the invention relates to compounds of formula I,wherein Y is of formulae XXIV, XXV, XXVII, XXXXI or XXXXII.

In another embodiment, the invention relates to compounds of formula I,wherein Y is of formula XXIV.

In yet another embodiment, the invention relates to compounds of formulaI, wherein Y is of formula XXV.

In yet another embodiment, the invention relates to compounds of formulaI, wherein Y is of formula XXVII.

In yet another embodiment, the invention relates to compounds of formulaI, wherein Y is of formula XXXXI.

In yet another embodiment, the invention relates to compounds of formulaI, wherein Y is of formula XXXXII.

In yet another embodiment, the invention relates to compounds of formulaI, wherein W is an oxygen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein W is a sulphur atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein V is a nitrogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein V is CH.

In yet another embodiment, the invention relates to compounds of formulaI, wherein T is a nitrogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein T is an oxygen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein each R⁵ is independently selected from the group consistingof Ar-oxy-C₁₋₆-alk(en/yn)yl, Ar-oxy-C₃₋₈-cycloalk(en)yl,Ar-oxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, acyl, —CO—NR⁶R^(6′),cyano, cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl andcyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein each R⁵ is independently selected from the group consistingof a C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy, C₃₋₈-cycloalk(en)yloxy,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy, Ar-oxy,C₁₋₆-alk(en/yn)yloxy-carbonyl, halogen, halo-C₁₋₆-alk(en/yn)yl,halo-C₃₋₈-cycloalk(en)yl, halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,NR⁷R^(7′), S—R⁸ and SO₂R⁸, or

-   two adjacent R⁵ together with the aromatic group form a 5-8 membered    ring, which optionally contains one or two heteroatoms.

When R⁵ represents NR⁷R^(7′)—C₁₋₆-alk(en/yn)yl,NR⁷R^(7′)—C₃₋₈-cycloalk(en)yl orNR⁷R^(7′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl then the nitrogen atomis linked to the remainder of the molecule via C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl or C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein each R⁵ is independently selected from the group consistingof a C₁₋₆-alk(en/yn)yl, Ar, C₁₋₆-alk(en/yn)yloxy, halogen, —NR⁷R^(7′),—S—R⁸ and —SO₂R⁸, or two adjacent R⁵ together with the aromatic groupform a 5-8 membered ring, which optionally contains one or twoheteroatoms.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein each R⁵ is independently selected from the group consistingof a C₁₋₆-alk(en/yn)yl, Ar, C₁₋₆-alk(en/yn)yloxy, Ar-oxy,C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, C₁₋₆-alk(en/yn)yloxy-carbonyl,halogen, halo-C₁₋₆-alk(en/yn)yl, NR⁷R^(7′), S—R⁸ and SO₂R⁸, or

-   two adjacent R⁵ together with the aromatic group form a 5-8 membered    ring, which optionally contains one or two heteroatoms.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is Ar—C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is Ar—C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is Ar—C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is Ar—C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is C₃₋₈ alk(en/yn)yloxy.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is C₃₋₈-cycloalk(en)yloxy.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is Ar-oxy.

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is Ar-oxy.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is C₁₋₆-alk(en/yn)yloxy-carbonyl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is C₁₋₆ alk(en/yn)yloxy-carbonyl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is a halogen atom.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is halo-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is halo-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is halo-C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is halo-C₃₋₈-cycloalk(en)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is NR⁷R^(7′).

In yet another embodiment, the invention relates to compounds of formulaI, wherein no R⁵ is NR⁷R^(7′).

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is S—R⁸.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one R⁵ is SO₂R⁸.

In yet another embodiment, the invention relates to compounds of formulaI, wherein two adjacent R⁵ together with the aromatic group form a 5-8membered ring, which optionally contains one or two heteroatoms.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein two adjacent R⁵ together form

-   —(CH₂)_(n′)—CH₂—, —CH═CH—(CH₂)_(m′)—, —CH₂—CH═CH—(CH₂)_(p′)—,    —CH═CH—CH═CH—, —(CH₂)_(n′)—O—, —O—(CH₂)_(m′)—O—,    —CH₂—O—(CH₂)_(p′)—O—, —CH₂—O—CH₂—O—CH₂—, —(CH₂)_(n′)—S—,    —S—(CH₂)_(m′)—S—, —CH₂—S—(CH₂)_(p′)—S—, —CH₂—S—CH₂—S—CH₂—,    —(CH₂)_(n′)—NH—, —NH—(CH₂)_(m′)—NH—, —CH₂—NH—(CH₂)_(p′)—NH—,    —CH═CH—NH—, —O—(CH₂)_(m′)—NH—, —CH₂—O—(CH₂)_(p′)—NH— or    —O—(CH₂)_(p′)—NH—CH₂—, —S—(CH₂)_(m′)—NH—, —N═CH—NH—, —N═CH—O— or    —N—CH—S—, wherein m′ is 1, 2 or 3, n′ is 2, 3 or 4 and p′ is 1 or 2.

In yet another embodiment, the invention relates to compounds of formulaI, wherein two adjacent R⁵ together form —CH₂—O—CH₂—.

In yet another embodiment, the invention relates to compounds of formulaI, wherein two adjacent R⁵ together form —CH═CH—CH═CH—.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R⁷ and R^(7′) are independently selected from the groupconsisting of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl andC₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R⁷ and R^(7′) are independently selected from the groupconsisting of hydrogen and C₁₋₆-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein one of R⁷ and R^(7′) are C₁₋₆-alk(en/yn)yl, typicallyC₁₋₃-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein both R⁷ and R^(7′) are C₁₋₆-alk(en/yn)yl, typicallyC₁₋₃-alk(en/yn)yl.

In yet another embodiment, the invention relates to compounds of formulaI, wherein R⁸ is selected from the group consisting of hydrogen,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl and Ar.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein R⁸ is selected from the group consisting of C₁₋₆-alk(en/yn)yland Ar.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein R⁸ is C₁₋₆-alk(en/yn)yl.

In a preferred embodiment, the invention relates to compounds of formulaI, wherein R⁸ is Ar.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is SO₂, q is 0 and R³ is C₁₋₆-alk(en/yn)yl, with theproviso that R³ is different from a methyl group.

In yet another embodiment, the invention relates to compounds of formulaI, wherein q is 0, R³ is a methyl group and X is different from SO₂.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is SO₂, q is 1 and U is different from O.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is O and X is different from SO₂.

In yet another embodiment, the invention relates to compounds of formulaI, wherein X is CO, q is 0 and R³ is C₁₋₆-alk(en/yn)yl, with the provisothat R³ is different from a methyl group.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is different from O, X is CO, q is 0 and R³ is amethyl group.

In yet another embodiment, the invention relates to compounds of formulaI, wherein s is 1, U is O, X is CO, q is 0 and R³ is C₁₋₆-alk(en/yn)yl,with the proviso that R³ is different from a methyl group.

The molecular weight of the compounds of the invention may vary fromcompound to compound. The molecular weight of a compound of formula I istypically more than 200 and less than 600, and more typically more than250 and less than 550.

One aspect of the invention, relates to compounds of general formulaXXIX and salts thereof:

wherein f, s, q, U, X, Z, R¹, R², R³ and R⁵ are as defined above,accordingly any of f, s, q, U, X, Z, R¹, R², R³, R⁴, R⁵, R⁶, R^(6′), R⁷,R^(7′), R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹² and R^(12′) are asdefined under formula I. Any of the embodiments related to formula I arealso embodiments of formula XXIX.

In another embodiment, the invention relates to compounds of the generalformula XXIX, wherein f is 0.

In another embodiment, the invention relates to compounds of the generalformula XXIX being substituted by one substituent R⁵, such as in theortho-, meta- or para-position.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXIX being substituted by two independently selected R⁵substituents, such as in the ortho- and para-position, in the meta- andpara-position and in the ortho- and meta-position.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXIX being substituted by three independently selectedR⁵ substituents.

Another aspect of the invention relates to compounds of the generalformula XXX or salts thereof:

wherein g, h, s, q, U, X, Z, R¹, R², R³ and R⁵ are as defined above,accordingly any of g, h, s, q, U, X, Z, R¹, R², R³, R⁵, R⁶, R^(6′)W R⁷,R^(7′), R⁸, R⁹, R⁹, R¹⁰, R¹¹, R¹² and R^(12′) are as defined underformula I. Any of the embodiments related to formula I are alsoembodiments of formula XXX.

In an embodiment, the invention relates to compounds of the generalformula XXX, wherein the nitrogen atom is attached to position 1 of thenaphtyl group via the methylene group.

In another embodiment, the invention relates to compounds of the generalformula XXX, wherein the nitrogen atom is attached to position 2 of thenaphtyl group via the methylene group.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXX, wherein g is 0, 1, 2 or 3, typically 0, 1 or 2.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXX, wherein h is 0, 1 or 2, typically 0 or 1.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXX, wherein both g and h are 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula X being substituted by one substituent R⁵, in aparticular aspect thereof g is 0 and h is 1 and in another particularaspect thereof g is 1 and h is 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXX being substituted by two independently selected R⁵substituents, in a particular aspect thereof g is 0 and h is 2, inanother particular aspect thereof g is 1 and h is 1 and in yet anotheraspect thereof g is 2 and h is 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXX being substituted by three independently selected R⁵substituents, in a particular aspect thereof g is 0 and h is 3, inanother particular aspect thereof g is 1 and h is 2, in yet anotheraspect thereof g is 2 and h is 1 and in yet another aspect thereof g is3 and h is 0.

Yet another aspect of the invention relates to compounds of the generalformula XXXI or salts thereof:

wherein a, s, q, U, W, X, Z, R¹, R², R³ and R⁵ are as defined above,accordingly any of a, s, q, U, W, X, Z, R¹, R², R³, R⁵, R⁶, R^(6′), R⁷,R^(7′), R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹² and R^(12′) are asdefined under formula I. Any of the embodiments related to formula I arealso embodiments of formula XXXI.

In an embodiment, the invention relates to compounds of the generalformula XXXI, wherein the nitrogen atom is attached to position 2 of theheteroaromatic group via the methylene group.

In another embodiment, the invention relates to compounds of the generalformula XXXI, wherein the nitrogen atom is attached to position 3 of theheteroaromatic group via the methylene group.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXI, wherein a is 0, 1 or 2.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXI, wherein a is 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXI being substituted by one substituent R⁵.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXI being substituted by two independently selected R⁵substituents.

Yet another aspect of the invention relates to compounds of the generalformula XXXII or salts thereof:

wherein b, c, s, q, U, W, X, Z, R¹, R², R³ and R⁵ are as defined above,accordingly any of b, e, s, q, U, W, X, Z, R¹, R², R³, R⁵, R⁶, R^(6′),R⁷, R^(7′), R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹² and R^(12′) are asdefined under formula I. Any of the embodiments related to formula I arealso embodiments of formula XXXII.

In one embodiment, the invention relates to compounds of the generalformula XXXII, wherein the nitrogen atom is attached to position 2 ofthe heteroaromatic group via the methylene group.

In another embodiment, the invention relates to compounds of the generalformula XXXII, wherein the nitrogen atom is attached to position 3 ofthe heteroaromatic group via the methylene group.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXII, wherein b is 0, 1, 2 or 3, typically 0, 1 or 2.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXII, wherein c is 0 or 1, typically 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXII, wherein both b and c are 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXII being substituted by one substituent R⁵, in anaspect thereof b is 0 and c is 1 and in another aspect thereof b is 1and c is 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXII being substituted by two independently selected R⁵substituents, in an aspect thereof b is 1 and c is 1 and in anotheraspect thereof b is 2 and c is 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXII being substituted by three independently selectedR⁵ substituents, in an aspect thereof b is 2 and c is 1 and in anotheraspect thereof b is 3 and c is 0.

Yet another aspect of the invention relates to compounds of the generalformula XXXIII or salts thereof:

wherein d, e, s, q, U, W, X, Z, R¹, R², R³ and R⁵ are as defined above,accordingly any of d, e, s, q, U, W, X, Z, R¹, R², R³, R¹, R⁶, R^(6′),R⁷, R^(7′), R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹² and R^(12′) are asdefined under formula I. Any of the embodiments related to formula I arealso embodiments of formula XXXIII.

In an embodiment, the invention relates to compounds of the generalformula XXXIII, wherein the nitrogen atom is attached to position 4 ofthe heteroaromatic group via the methylene group.

In another embodiment, the invention relates to compounds of the generalformula XXXIII, wherein the nitrogen atom is attached to position 5 ofthe heteroaromatic group via the methylene group.

In an embodiment, the invention relates to compounds of the generalformula XXXIII, wherein the nitrogen atom is attached to position 6 ofthe heteroaromatic group via the methylene group.

In another embodiment, the invention relates to compounds of the generalformula XXXIII, wherein the nitrogen atom is attached to position 7 ofthe heteroaromatic group via the methylene group.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXIII, wherein d is 0, 1 or 2, typically 0 or 1.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXIII, wherein e is 0, 1 or 2.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXIII, wherein both d and e are 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXIII being substituted by one substituent R⁵, in aparticular aspect thereof d is 0 and e is 1 and in another particularaspect thereof d is 1 and e is 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXIII being substituted by two independently selectedR⁵ substituents, in a particular aspect thereof d is 0 and e is 2, inanother particular aspect thereof d is 1 and e is 1 and in yet anotheraspect thereof d is 2 and e is 0.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXIII being substituted by three independently selectedR⁵ substituents, in an aspect thereof d is 1 and e is 2, in anotheraspect thereof d is 2 and e is 1 and in yet another aspect thereof d is3 and e is 0.

Yet another aspect of the invention relates to compounds of the generalformula XXXXIII or salts thereof:

wherein dd, s, q, U, V, X, Z, R¹, R², R³ and R⁵ are as defined underformula I. Any of the embodiments related to formula I are alsoembodiments of formula XXXXIII.

In another embodiment, the invention relates to compounds of the generalformula XXXIII, wherein V is a carbon atom to which the nitrogen atom isattached via the methylene group.

In an embodiment, the invention relates to compounds of the generalformula XXXXIII, wherein the nitrogen atom is attached to the carbonatom, which is indicated with “1”, via the methylene group.

In an embodiment, the invention relates to compounds of the generalformula XXXXIII, wherein the nitrogen atom is attached to the carbonatom, which is indicated with “2”, via the methylene group.

In another embodiment, the invention relates to compounds of the generalformula XXXXIII, wherein the nitrogen atom is attached to the carbonatom, which is indicated with “3”, via the methylene group.

In another embodiment, the invention relates to compounds of the generalformula XXXXIII, wherein the nitrogen atom is attached to the carbonatom, which is indicated with “4”, via the methylene group.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXXIII, wherein dd is 0, 1 or 2, typically 0 or 1. Inone aspect of the invention dd is 0. In another aspect of the inventiondd is 0.

Yet another aspect of the invention relates to compounds of the generalformula XXXXIV or salts thereof:

wherein aa, s, q, T, U, X, Z, R¹, R², R³ and R⁵ are as defined underformula I. Any of the embodiments related to formula I are alsoembodiments of formula XXXXIV.

In an embodiment, the invention relates to compounds of the generalformula XXXXIV, wherein T is a nitrogen atom to which the nitrogen atomis attached via the methylene group.

In an embodiment, the invention relates to compounds of the generalformula XXXXIV, wherein the nitrogen atom is attached to the carbonatom, which is indicated with “1”, via the methylene group.

In an embodiment, the invention relates to compounds of the generalformula XXXXIV, wherein the nitrogen atom is attached to the carbonatom, which is indicated with “2”, via the methylene group.

In another embodiment, the invention relates to compounds of the generalformula XXXXIV, wherein the nitrogen atom is attached to the carbonatom, which is indicated with “3”, via the methylene group.

In yet another embodiment, the invention relates to compounds of thegeneral formula XXXI, wherein aa is 0, 1 or 2. In one embodiment aa is0. In another embodiment, the general formula XXXXIV are substituted byone substituent R⁵. In yet another embodiment, the compounds of thegeneral formula XXXI are substituted by two independently selected R⁵substituents.

In one particular embodiment, the present invention relates tosubstituted p-diaminobenzene derivatives of the general formula Ia

wherein

-   s is 0 or 1;-   U is O, S, SO₂, SO₂NR¹¹, CO—O or CO—NR¹¹; wherein R¹¹ is selected    from the group consisting of hydrogen, C₁₋₆-alk(en/yn)yl,    C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; or R²    and R¹¹ together with the nitrogen atom form a 5-8 membered    saturated or unsaturated ring which optionally contains 1, 2 or 3    further heteroatoms;-   q is 0 or 1;-   X is CO or SO₂; with the proviso that q is 0 when X is SO₂;-   Z is O or S;-   R¹ is selected from the group consisting of hydrogen,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, acyl,    hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano-C₁₋₆-alk(en/yn)yl,    cyano-C₃₋₈-cycloalk(en)yl and    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl;-   R² is selected from the group consisting of hydrogen,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,    Ar—C₃₋₈-cycloalk(en)yl, Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    acyl, hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, halogen,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano,    cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl,    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    NR¹⁰R^(10′)—C₁₋₆-alk(en/yn)yl, NR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl and    NR¹⁰R¹⁰—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; wherein R¹⁰ and    R^(10′) are independently selected from the group consisting of    hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, hydroxy-C₁₋₆-alk(en/yn)yl,    hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano-C₁₋₆-alk(en/yn)yl,    cyano-C₃₋₈-cycloalk(en)yl and    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, or R¹⁰ and R^(10′)    together with the nitrogen atom form a 5-8 membered saturated or    unsaturated ring which optionally contains 1, 2 or 3 further    heteroatoms;-   provided that when R² is halogen or cyano then s is 0; and-   provided that U is O or S when s is 1 and R² is a hydrogen atom or    acyl;-   R³ is selected from the group consisting of C₁₋₆-alk(en/yn)yl,    C₃₋₈-cycloalk(en)yl, heterocycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,    Ar—C₃₋₈-cycloalk(en)yl, Ar-heterocycloalk(en)yl,    Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    Ar—C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    Ar—C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,    C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,    C₃₋₈-cycloalk(en)yloxy-C₁₋₆-alk(en/yn)yl,    C₁₋₆-alk(en/yn)yloxy-C₃₋₈-cycloalk(en)yl,    C₁₋₆-alk(en/yn)yloxy-heterocycloalk(en)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,    Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,    C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆ alk(en/yn)yl,    C₃₋₈-cycloalk(en)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,    hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-heterocycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    hydroxy-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    hydroxy-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-heterocycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    halo-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, halo-C₁₋₆    alk(en/yn)yl-Ar, halo-C₃₋₈-cycloalk(en)yl-Ar,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl-Ar,    halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl-Ar,    cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl,    cyano-heterocycloalk(en)yl,    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    cyano-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    cyano-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,    acyl-C₁₋₆-alk(en/yn)yl, acyl-C₃₋₈-cycloalk(en)yl,    acyl-heterocycloalk(en)yl,    acyl-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    acyl-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,    acyl-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, —NR¹²R^(12′); wherein    R¹² and R^(12′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, hydroxy-C₁₋₆-alk(en/yn)yl,    hydroxy-C₃₋₈-cycloalk(en)yl,    hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, cyano-C₁₋₆-alk(en/yn)yl,    cyano-C₃₋₈-cycloalk(en)yl and    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, or R¹² and R^(12′)    together with the nitrogen atom form a 5-8 membered saturated or    unsaturated ring which optionally contains 1, 2 or 3 further    heteroatoms; and-   Y represents a group of formula XXIV, XXV, XXVI, XXVII or XXVIII:

wherein

-   the line represents a bond attaching the group represented by Y to    the carbon atom;-   W is O or S;-   a is 0, 1, 2 or 3;-   b is 0, 1, 2, 3 or 4;-   c is 0 or 1;-   d is 0, 1, 2 or 3;-   e is 0, 1 or 2;-   f is 0, 1, 2, 3, 4 or 5;-   g is 0, 1, 2, 3 or 4;-   h is 0, 1, 2 or 3; and-   each R⁵ is independently selected from the group consisting of a    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,    acyl, C₁₋₆-alk(en/yn)yloxy, C₃₋₈-cycloalk(en)yloxy,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy, halogen,    halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,    halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, —CO—NR⁶R⁶′, cyano,    cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl,    cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, —NR⁷R^(7′), —S—R⁸ and    —SO₂R⁸, or two adjacent R⁵ together with the aromatic group form a    5-8 membered ring which optionally contains one or two heteroatoms;-   R⁶ and R^(6′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl and Ar;-   R⁷ and R^(7′) are independently selected from the group consisting    of hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar and acyl; and-   R⁸ is selected from the group consisting of hydrogen,    C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar and —NR⁹R^(9′); wherein R⁹    and R^(9′) are independently selected from the group consisting of    hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl and    C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl;-   or salts thereof.

In one embodiment, the compounds of the following list and salts thereofare preferred:

-   {4-[(Benzofuran-2-ylmethyl)-amino]-2-methylphenyl}-carbamic acid    propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid ethyl ester;-   {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid ethyl ester;-   {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid ethyl ester;-   [4-(4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid ethyl    ester;-   [4-(4-Fluoro-benzylamino)-2-methylphenyl]-carbamic acid propyl    ester;-   (4-{[4-(4-Chloro-benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino}-2-methylphenyl)-carbamic    acid propyl ester;-   {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid propyl ester;-   {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid propyl ester;-   {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   [4-(4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid propyl    ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid ethyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid ethyl ester;-   {4-[Benzo[b]thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid ethyl ester;-   [2-Chloro-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid ethyl    ester;-   [2-Chloro-4-(4-fluoro-benzylamino)-phenyl]-carbamic acid propyl    ester;-   2-Chloro-4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino}-phenyl)-carbamic    acid propyl ester;-   {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {4-[(Benzofuran-2-yl-4-ethyl)-amino]-2-chlorophenyl}-carbamic acid    propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamic    acid ethyl ester;-   {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-carbamic    acid methyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-carbamic    acid isopropyl ester;-   {4-[(4-Fluoro-benzyl)-(methyl)amino]-2-methoxyphenyl}-carbamic acid    propyl ester;-   [4-(Benzo[b]thiophen-2-ylmethyl-(methyl)amino)-2-methoxy-phenyl]-carbamic    acid propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methoxy-phenyl}-carbamic    acid propyl ester;-   {4[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-methoxy-phenyl}-carbamic    acid propyl ester;-   {2-Methoxy-4-[methyl-(5-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(4-Fluorobenzyl)-(methyl)-amino]-2-isopropoxyphenyl}-carbamic    acid ethyl ester;-   [4-(3-Fluorobenzylamino)-2-methoxyphenyl]-carbamic acid ethyl ester;-   [4-(4-Isopropylbenzylamino)-2-methoxyphenyl]-carbamic acid ethyl    ester;-   {2-Methoxy-4-[(3-methylthiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid ethyl ester;-   [4-(2,4-Difluorobenzylamino)-2-methoxyphenyl]-carbamic acid ethyl    ester;-   [2-Cyclopentyloxy-4-(4-methoxybenzylamino)-phenyl]-carbamic acid    ethyl ester;-   [2-Cyclopentyloxy-4-(3-fluoro-2-methylbenzylamino)-phenyl]-carbamic    acid ethyl ester;-   [4-(3-Fluoro-2-methylbenzylamino)-2-phenethyloxyphenyl]-carbamic    acid ethyl ester;-   [2-Benzyloxy-4-(3-fluoro-2-methylbenzylamino)-phenyl]-carbamic acid    ethyl ester;-   [2-Benzyloxy-4-(4-methylsulfanylbenzylamino)-phenyl]-carbamic acid    ethyl ester;-   {4-[Benzo[b]thiophen-3-dimethyl)-amino]-2-cyclopentyloxyphenyl}-carbamic    acid ethyl ester;-   [4-(3-Fluoro-2-methylbenzylamino)-2-isopropoxyphenyl]-carbamic acid    ethyl ester;-   [2-Benzyloxy-4-(3-methoxybenzylamino)-phenyl]-carbamic acid ethyl    ester;-   {4-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-2-isopropoxyphenyl}-carbamic    acid ethyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid    propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid    propyl ester;-   [2-Cyano-4-(4-isopropylbenzylamino)-phenyl]-carbamic acid ethyl    ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-carbamic    acid propyl ester;-   {4-[(4-Isopropylbenzyl)-(methyl)amino]-2-methylphenyl}-carbamic acid    propyl ester;-   {2-Methyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {2-Methyl-4-[methyl-(4-methylsulfanyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-chlorophenyl}-carbamic    acid ethyl ester;-   {2-Chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic    acid ethyl ester;-   {2-Chloro-4-[methyl-(4-methylsulfanyl-benzyl)-amino]-phenyl}-carbamic    acid ethyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {2-Chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4[(4-Isopropyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[Methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[Methyl-(4-methylsulfanyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}carbamic    acid propyl ester;-   {4-[(4-Isopropyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[Methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[Methyl-(4-methylsulfanyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-cyanophenyl}-carbamic    acid propyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-cyanophenyl}-carbamic    acid propyl ester;-   {2-Cyano-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[(5-bromo-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[(4-isopropylbenzyl)-(methyl)amino]-phenyl}-carbamic acid    propyl ester;-   {2-Bromo-4-[(4-tert-butyl-benzyl)-(methyl)amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   [2-Iodo-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid propyl    ester;-   [4-(4-tert-Butyl-benzylamino)-2-iodophenyl]-carbamic acid propyl    ester;-   [2-Iodo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   [2-Iodo-4-(4-methylsulfanyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   {2-Iodo-4-[4-(4-methylpiperazin-1-yl)-benzylamino]-phenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   [4-(4-tert-Butyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid ethyl ester;-   [4-(4-Methylsulfanyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid ethyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   [4-(4-Isopropylbenzylamino)-2-trifluoromethyl-phenyl]-carbamic acid    propyl ester;-   [4-(4-tert-Butyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid propyl ester;-   [2-Trifluoromethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic    acid propyl ester;-   [4-(4-Dimethylamino-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid propyl ester;-   [4-(4-Methylsulfanyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamic    acid propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamic    acid propyl ester;-   [2-Cyano-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   {2-Bromo-4-[(5-bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   [2-Bromo-4-(4-isopropylbenzylamino)-phenyl]-carbamic acid propyl    ester;-   [2-Bromo-4-(4-tert-butyl-benzylamino)-phenyl]-carbamic acid propyl    ester;-   [2-Bromo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   [2-Bromo-4-(4-methylsulfanyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   N-{4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-butyramide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-butyramide;-   N-[4-(4-Isopropylbenzylamino)-2-methoxyphenyl]-butyramide;-   N-[4-(4-tert-Butyl-benzylamino)-2-methoxyphenyl]-butyramide;-   N-[2-Methoxy-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-furan-2-yl-phenyl}-carbamic    acid propyl ester;-   [2-Furan-2-yl-4-(4-isopropylbenzylamino)-phenyl]-carbamic acid    propyl ester;-   [5-(4-Fluorobenzylamino)-biphenyl-2-yl]-carbamic acid propyl ester;-   {5-[(5-Chloro-thiophen-2-ylmethyl)-amino]-biphenyl-2-yl}-carbamic    acid propyl ester;-   [5-(4-Isopropylbenzylamino)-biphenyl-2-yl]-carbamic acid propyl    ester;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-phenylacetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3,3-dimethylbutyramide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-phenylpropionamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-butyramide;-   Pentanoic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   Cyclopropanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   Cyclobutanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   Cyclopentanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   Cyclohexanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-thiophen-2-yl-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(3-methoxy)-phenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-chloro-phenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-methoxy-phenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-fluoro-phenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-cyclohexylpropionamide;-   N-{2-Chloro-4[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2-dimethylpropionamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-phenoxyacetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-phenylacetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-3,3-dimethylbutyramide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-butyramide;-   Pentanoic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   Cyclopropanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   Cyclobutanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   Cyclopentanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   Cyclohexanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-thiophen-2-yl-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(3-methoxyphenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4-chlorophenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4-methoxyphenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4-fluorophenyl)-acetamide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-3-cyclohexylpropionamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-2,2-dimethylpropionamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-2-phenylacetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-3,3-dimethylbutyramide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-3-phenylpropionamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-ylmethyl-phenyl}-butyramide;-   2,2,2-Trichloro-N-{4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-acetamide;-   Cyclopropanecarboxylic acid    {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-amide;-   Cyclobutanecarboxylic acid    {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide;-   Cyclopentanecarboxylic acid    {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide;-   Cyclohexanecarboxylic acid    {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-thiophen-2-yl-acetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(3-methoxyphenyl)-acetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-malonamic    acid methyl ester;-   2-(4-Chlorophenyl)-N-{4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-acetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(4-methoxyphenyl)-acetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(4-fluorophenyl)-acetamide;-   N-{4[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-3-cyclohexylpropionamide;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid phenyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid benzyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid isobutyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid butyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid hexyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid 4-nitrobenzyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid but-3-enyl ester;-   {2-Chloro-4[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid but-2-ynyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid 2,2-dimethylpropyl ester;-   {2,2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid 2-chlorobenzyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid 3-chloropropyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid 2-benzyloxyethyl ester;-   3-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-1-methyl-1-propyl-urea;-   1-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-(2-fluorophenyl)-urea;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2,2,2-trifluoroacetamide;    and-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide.-   In another embodiment, the compounds of the following list and salts    thereof are preferred:-   {4-[(Benzofuran-2-ylmethyl)-amino]-2-methylphenyl}-carbamic acid    propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid ethyl ester;-   {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid ethyl ester;-   {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid ethyl ester;-   [4-(4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid ethyl    ester;-   [4-(4-Fluoro-benzylamino)-2-methylphenyl]-carbamic acid propyl    ester;-   (4-{[4-(4-Chloro-benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino}-2-methylphenyl)-carbamic    acid propyl ester;-   {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    propyl ester;-   {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid propyl ester;-   {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   [4-(4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid propyl    ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid ethyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid ethyl ester;-   {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid ethyl ester;-   [2-Chloro-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid ethyl    ester;-   [2-Chloro-4-(4-fluoro-benzylamino)-phenyl]-carbamic acid propyl    ester;-   2-Chloro-4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino}-phenyl)-carbamic    acid propyl ester;-   {4[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {4[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {4-[(Benzofuran-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic acid    propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamic    acid ethyl ester;-   {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-carbamic    acid methyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-carbamic    acid isopropyl ester;-   {4-[(4-Fluoro-benzyl)-(methyl)amino]-2-methoxyphenyl}-carbamic acid    propyl ester;-   [4-(Benzo[b]thiophen-2-ylmethyl-(methyl)amino)-2-methoxy-phenyl]-carbamic    acid propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methoxy-phenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-methoxy-phenyl}-carbamic    acid propyl ester;-   {2-Methoxy-4-[methyl-(5-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(4-Fluorobenzyl)-(methyl)-amino]-2-isopropoxyphenyl}-carbamic    acid ethyl ester;-   [4-(3-Fluorobenzylamino)-2-methoxyphenyl]-carbamic acid ethyl ester;-   [4-(4-Isopropylbenzylamino)-2-methoxyphenyl]-carbamic acid ethyl    ester;-   {2-Methoxy-4-[(3-methylthiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid ethyl ester;-   [4-(2,4-Difluorobenzylamino)-2-methoxyphenyl]-carbamic acid ethyl    ester;-   [2-Cyclopentyloxy-4-(4-methoxybenzylamino)-phenyl]-carbamic acid    ethyl ester;-   [2-Cyclopentyloxy-4-(3-fluoro-2-methylbenzylamino)-phenyl]-carbamic    acid ethyl ester;-   [4-(3-Fluoro-2-methylbenzylamino)-2-phenethyloxyphenyl]-carbamic    acid ethyl ester;-   [2-Benzyloxy-4-(3-fluoro-2-methylbenzylamino)-phenyl]-carbamic acid    ethyl ester;-   [2-Benzyloxy-4-(4-methylsulfanylbenzylamino)-phenyl]-carbamic acid    ethyl ester;-   {4-[(Benzo[b]thiophen-3-ylmethyl)-amino]-2-cyclopentyloxyphenyl}-carbamic    acid ethyl ester;-   [4-(3-Fluoro-2-methylbenzylamino)-2-isopropoxyphenyl]-carbamic acid    ethyl ester;-   [2-Benzyloxy-4-(3-methoxybenzylamino)-phenyl]-carbamic acid ethyl    ester;-   {4-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-2-isopropoxyphenyl}-carbamic    acid ethyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid    propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid    propyl ester;-   [2-Cyano-4-(4-isopropylbenzylamino)-phenyl]-carbamic acid ethyl    ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-carbamic    acid propyl ester;-   {4-[(4-Isopropylbenzyl)-(methyl)amino]-2-methylphenyl}-carbamic acid    propyl ester;-   {2-Methyl-4-[methyl-(4-trifluorophenyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {2-Methyl-4-[methyl-(4-methylsulfanyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-chlorophenyl}-carbamic    acid ethyl ester;-   {2-Chloro-4[c    ethyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic acid ethyl    ester;-   {2-Chloro-4[methyl-(4-methylsulfanyl-benzyl)-amino]-phenyl}-carbamic    acid ethyl ester:-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-chlorophenyl}-carbamic    acid propyl ester;-   {2-Chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[(4-Isopropyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[Methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[Methyl-(4-methylsulfanyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[(4-Isopropyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}carbamic    acid propyl ester;-   {4-[Methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[Methyl-(4-methylsulfanyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-cyanophenyl}-carbamic    acid propyl ester;-   {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-cyanophenyl}-carbamic    acid propyl ester;-   {2-Cyano-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[(5-bromo-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[(4-isopropylbenzyl)-(methyl)amino]-phenyl}-carbamic acid    propyl ester;-   {2-Bromo-4-[(4-tert-butyl-benzyl)-(methyl)amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic    acid propyl ester;-   [2-Iodo-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid propyl    ester;-   [4-(4-tert-Butyl-benzylamino)-2-iodophenyl]-carbamic acid propyl    ester;-   [2-Iodo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   [2-Iodo-4-(4-methylsulfanyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   {2-Iodo-4-[4-(4-methylpiperazin-1-yl)-benzylamino]-phenyl}-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid ethyl ester;-   [4-(4-tert-Butyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid ethyl ester;-   [4-(4-Methylsulfanyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid ethyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl}-carbamic    acid propyl ester;-   [4-(4-Isopropylbenzylamino)-2-trifluoromethyl-phenyl]-carbamic acid    propyl ester;-   [4-(4-tert-Butyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid propyl ester;-   [2-Trifluoromethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic    acid propyl ester;-   [4-(4-Dimethylamino-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid propyl ester;-   [4-(4-Methylsulfanyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic    acid propyl ester;-   {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamic    acid propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamic    acid propyl ester;-   [2-Cyano-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   {2-Bromo-4-[(5-bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   {2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic    acid propyl ester;-   [2-Bromo-4-(4-isopropylbenzylamino)-phenyl]-carbamic acid propyl    ester;-   [2-Bromo-4-(4-tert-butyl-benzylamino)-phenyl]-carbamic acid propyl    ester;-   [2-Bromo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   [2-Bromo-4-(4-methylsulfanyl-benzylamino)-phenyl]-carbamic acid    propyl ester;-   N-{4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-butyramide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-butyramide;-   N-[4-(4-Isopropylbenzylamino)-2-methoxyphenyl]-butyramide;-   N-[4-(4-tert-Butyl-benzylamino)-2-methoxyphenyl]-butyramide;-   N-[2-Methoxy-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-furan-2-yl-phenyl}-carbamic    acid propyl ester;-   [2-Furan-2-yl-4-(4-isopropylbenzylamino)-phenyl]-carbamic acid    propyl ester;-   [5-(4-Fluorobenzylamino)-biphenyl-2-yl]-carbamic acid propyl ester;-   {5-[(5-Chloro-thiophen-2-ylmethyl)-amino]-biphenyl-2-yl}-carbamic    acid propyl ester;-   [5-(4-Isopropylbenzylamino)-biphenyl-2-yl]-carbamic acid propyl    ester;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-phenylacetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-yl-ethyl)-(methyl)amino]-phenyl}-3,3-dimethylbutyramide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl-(methyl)amino]-phenyl}-3-phenylpropionamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-butyramide;-   Pentanoic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   Cyclopropanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   Cyclobutanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   Cyclopentanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   Cyclohexanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-thiophen-2-yl-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-yl    ethyl)-(ethyl)amino]-phenyl}-2-(3-methoxy-phenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-chloro-phenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-methoxy-phenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-fluoro-phenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-cyclohexylpropionamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2-dimethylpropionamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-phenoxyacetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-phenylacetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-3,3-dimethylbutyramide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-butyramide;-   Pentanoic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   Cyclopropanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   Cyclobutanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   Cyclopentanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   Cyclohexanecarboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-thiophen-2-yl-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(3-methoxyphenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4-chlorophenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4-methoxyphenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4-fluorophenyl)-acetamide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-3-cyclohexylpropionamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-2,2-dimethylpropionamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-2-phenylacetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-3,3-dimethylbutyramide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-3-phenylpropionamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-butyramide;-   2,2,2-Trichloro-N-{4-[(5-chloro-thiophen-2-ylmethyl)-(ethyl)amino]-2-methyl-phenyl}-acetamide;-   Cyclopropanecarboxylic acid    {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-amide;-   Cyclobutanecarboxylic acid    {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide;-   Cyclopentanecarboxylic acid    {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide;-   Cyclohexanecarboxylic acid    {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-thiophen-2-yl-acetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(3-methoxyphenyl)-acetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-malonamic    acid methyl ester;-   2-(4-Chlorophenyl)-N-{4-[(5-chloro-thiophen-2-ylmethyl)-(ethyl)amino]-2-methylphenyl}-acetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(4-methoxyphenyl)-acetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(4-fluorophenyl)-acetamide;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-3-cyclohexylpropionamide;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid phenyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid benzyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid isobutyl ester;-   {2-Chloro-4[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid butyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid hexyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-ylmethyl)-(methyl)amino]-phenyl}carbamic    acid 4-nitrobenzyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid but-3-enyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid but-2-ynyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid 2,2-dimethylpropyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid 2-chlorobenzyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid 3-chloropropyl ester;-   {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic    acid 2-benzyloxyethyl ester;-   3-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-1-methyl-1-propyl-urea;-   1-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-(2-fluorophenyl)-urea;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2,2,2-trifluoroacetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide;-   N-{5-[(5-Chloro-thiophen-2-ylmethyl)-amino]-4′-dimethylamino-biphenyl-2-yl}-2-(4-fluorophenyl)-acetamide;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-chlorophenyl)-acetamide;-   [4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2-methylphenyl]-carbamic    acid ethyl ester;-   2-(4-Fluorophenyl)-N-{2-methyl-4-[(6-p-tolyloxypyridin-3-ylmethyl);    amino]-phenyl}-acetamide;-   N-[2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide;-   2-(4-Fluorophenyl)-N-{2-methyl-4[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-phenyl}-acetamide;-   Pentanoic acid    {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide;-   3,3-Dimethyl-N-{2-methyl-4-[(6-p-tolyloxypyridin-3-ylmethyl)-amino]-phenyl}-butyramide;-   [2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid    ethyl ester;-   N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-chlorophenyl)-propionamide;-   [4-(4-Chloro-benzylamino)-2-methylphenyl]-carbamic acid ethyl ester;-   {4[(6-Methoxy-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid propyl ester;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-quinolin-3-yl-phenyl}-carbamic    acid ethyl ester;-   {4-[5-Dimethylamino-3-methyl-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid propyl ester;-   3,3-Dimethyl-N-{2-methyl-4-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-phenyl}-butyramide;-   N-(4-{[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]-amino}-2-methylphenyl)-2-(4-fluorophenyl)-acetamide;-   {2-Benzyloxy-4-[(4-fluorobenzyl)-(ylmethyl)amino]-phenyl}-thiocarbamic    acid S-ethyl ester;-   {2-Cyclopentyloxy-4[(4-fluorobenzyl)-(methyl)amino]-phenyl}-thiocarbamic    acid S-ethyl ester;-   N-{4-[(6-Chloropyridin-3-ylmethyl)-amino]-2-methylphenyl}-2-(4-fluorophenyl)-acetamide;-   {4-[(7-Dimethylamino-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid propyl ester;-   1-{2-Cyclopentyloxy-4-[(4-fluorobenzyl)-(ylmethyl)amino]-phenyl}-3-ethyl-urea;-   2-Amino-4-methyl-pentanoic acid    [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide;-   {4-[(6-Methoxy-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic    acid ethyl ester;-   2-Amino-4-methyl-pentanoic acid    [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide;-   2-(4-Fluorophenyl)-N-{2-methyl-4-[(4-methyl-2-phenylpyridin-5-ylmethyl)-amino]-phenyl}-acetamide;-   3,3-Dimethyl-N-{2-methyl-4-[(2-phenylpyrimidin-5-ylmethyl-amino]-phenyl}-butyramide;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-pyridin-3-yl-phenyl}-carbamic    acid ethyl ester;-   1-Amino-cyclopropanecarboxylic acid    [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-pyridin-4-yl-phenyl}-carbamic    acid ethyl ester;-   N-[2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-piperidin-1-yl-acetamide;-   N-(4-{[5-(4-Chlorophenoxy)-1,3-dimethyl-1H-pyrazol-4-ylmethyl]-amino}-2-methylphenyl)-2,2-dimethylpropionamide;-   2,2-Dimethyl-N-{2-methyl-4-[(6-phenoxypyridin-3-ylmethyl)-amino]-phenyl}-propionamide;-   N-[2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-pyrrolidin-1-yl-acetamide;-   [4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-(6-methoxypyridin-3-yl)-phenyl]-carbamic    acid ethyl ester;-   4-[(3-Methyl-4-propoxycarbonylamino-phenylamino)-methyl]-benzoic    acid methyl ester;-   N-[2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-morpholin-4-yl-acetamide;-   2,2-Dimethyl-N-{2-methyl-4-[(3-methyl-5-phenylisoxazol-4-ylmethyl)-amino]-phenyl}-propionamide;-   {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-iodophenyl}-carbamic    acid ethyl ester;-   N-{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-iodophenyl}-2-(4-fluorophenyl)-acetamide;    and-   {4[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-quinolin-5-yl-phenyl}-carbamic    acid ethyl ester.

According to one embodiment, the invention relates to a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carriersor diluents and a compound of formula I wherein s, q, U, X, Z, Y, R¹, R²and R³ are as defined above, accordingly any of a, b, c, d, e, f, g, h,s, q, U, X, Z, Y W, R¹, R², R³, R⁵, R⁶, R^(6′), R⁷, R^(7′), R⁸, R⁹,R^(9′), R¹⁰, R^(10′), R¹¹, R¹² and R^(12′) are as defined under formulaI, or salts thereof. Pharmaceutical compositions of the invention maythus comprise one or more compounds of formula I or salts thereof, suchas one compound of formula I or a salt thereof; or two compounds offormula I or salts thereof; or three compounds of formula I or saltsthereof.

According to one embodiment, the invention relates to a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carriersor diluents and a compound of formula XXIX wherein f, s, q, U, X, Z, R¹,R², R³ and R⁵ are as defined above, accordingly any of f, s, q, U, X, Z,R¹, R², R³, R⁵, R⁶, R^(6′), R⁷, R^(7′), R⁸, R⁹, R^(9′), R¹⁰, R^(10′),R¹¹, R¹² and R^(12′) are as defined under formula XXIX. Pharmaceuticalcompositions of the invention may thus comprise one or more compounds offormula XXIX or salts thereof, such as one compound of formula XXIX or asalt thereof; or two compounds of formula XXIX or salts thereof; orthree compounds of formula XXIX or salts thereof.

According to one embodiment, the invention relates to a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carriersor diluents and a compound of formula XXX wherein g, h, s, q, U, X, Z,R¹, R², R³ and R⁵ are as defined above, accordingly any of g, h, s, q,U, X, Z, R¹, R², R³, R⁵, R⁶, R^(6′), R⁷, R^(7′), R⁸, R⁹, R^(9′), R¹⁰,R^(10′), R¹¹, R¹² and R^(12′) are as defined under formula XXX.Pharmaceutical compositions of the invention may thus comprise one ormore compounds of formula XXX or salts thereof, such as one compound offormula XXX or a salt thereof; or two compounds of formula XXX or saltsthereof; or three compounds of formula XXX or salts thereof.

According to one embodiment, the invention relates to a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carriersor diluents and a compound of formula XXXI wherein a, s, q, U, W, X, Z,R¹, R², R³ and R⁵ are as defined above, accordingly any of a, s, q, U,W, X, Z, R¹, R², R³, R⁵, R⁶, R^(6′), R⁷, R^(7′), R⁸, R⁹, R^(9′), R¹⁰,R^(10′), R¹¹, R¹² and R^(12′) are as defined under formula XI.Pharmaceutical compositions of the invention may thus comprise one ormore compounds of formula XXXI or salts thereof, such as one compound offormula XXXI or a salt thereof; or two compounds of formula XXXI orsalts thereof; or three compounds of formula XXXI or salts thereof.

According to one embodiment, the invention relates to a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carriersor diluents and a compound of formula XXXII wherein b, c, s, q, U, W, X,Z, R¹, R², R³ and R⁵ are as defined above, accordingly any of b, c, s,q, U, W, X, Z, R¹, R², R³, R⁵, R⁶, R^(6′), R⁷, R^(7′), R⁸, R⁹, R^(9′),R¹⁰, R^(10′), R¹¹, R¹² and R^(12′) areas defined under formula XXXII.Pharmaceutical compositions of the invention may thus comprise one ormore compounds of formula XXXII or salts thereof, such as one compoundof formula XXXII or a salt thereof; or two compounds of formula XXXII orsalts thereof; or three compounds of formula XXXII or salts thereof.

According to one embodiment, the invention relates to a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carriersor diluents and a compound of formula XXXIII wherein d, e, s, q, U, W,X, Z, R¹, R², R³ and R⁵ are as defined above, accordingly any of d, e,s, q, U, W, X, Z, R¹, R², R³, R⁵, R⁶, R^(6′), R⁷, R^(7′), R⁸, R⁹,R^(9′), R¹⁰, R^(10′), R¹¹, R¹² and R^(12′) are as defined under formulaXXXIII. Pharmaceutical compositions of the invention may thus compriseone or more compounds of formula XXXIII or salts thereof, such as onecompound of formula XXXIII or a salt thereof; or two compounds offormula XXXIII or salts thereof; or three compounds of formula XXXIII orsalts thereof.

The invention thus provides a pharmaceutical composition for oral orparenteral administration, said pharmaceutical composition comprising atleast one compound of formula I or XXIX or XXX or XXXI or XXXII orXXXXIII or a salt thereof in a therapeutically effective amount togetherwith one or more pharmaceutically acceptable carriers or diluents.

In one aspect, the compounds of the invention may be administered as theonly therapeutically effective compound.

In another aspect the compounds of the invention may be administered asa part of a combination therapy, i.e. the compounds of the invention maybe administered in combination with other therapeutically effectivecompounds having e.g. anti-convulsive properties. The effects of suchother compounds having anti-convulsive properties may include but not belimited to activities on:

-   -   ion channels such as sodium, potassium, or calcium channels    -   the excitatory amino acid systems e.g. blockade or modulation of        NMDA receptors    -   the inhibitory neurotransmitter systems e.g. enhancement of GABA        release, or blockade of GABA-uptake or    -   membrane stabilisation effects.

Current anti-convulsive medications include, but are not limited to,tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin,pregabalin, ethosuximide, levetiracetam, phenytoin, topiramate,zonisamide as well as members of the benzodiazepine and barbiturateclass.

In one aspect, the compounds of the invention have been found to haveeffect on potassium channels of the KCNQ family, in particular the KCNQ2subunit.

In one embodiment, the invention relates to the use of one or morecompounds according to the invention in a method of treatment. Thedisorder or condition to be prevented, treated or inhibited isresponsive to an increased ion flow in a potassium channel such as theKCNQ family potassium ion channels. Such disorder or condition ispreferably a disorder or condition of the central nervous system.

The compounds of the invention are considered useful for increasing ionflow in a voltage-dependent potassium channel in a mammal such as ahuman.

The compounds of the invention are considered useful for the prevention,treatment or inhibition of a disorder or condition being responsive toan increased ion flow in a potassium channel such as the KCNQ familypotassium ion channels. Such disorder or condition is preferably adisorder or condition of the central nervous system.

The compounds of the invention are thus considered useful forpreventing, treating or inhibiting disorders or diseases such as seizuredisorders, neuropathic and migraine pain disorders, anxiety disordersand neurodegenerative disorders.

Accordingly, the compounds of the invention are considered useful forthe prevention, treatment or inhibition of disorders or conditions suchas convulsions, epilepsy, anxiety disorders, neuropathic pain andneurodegenerative disorders.

According to one particular embodiment, the compounds of the inventionare thus considered to be useful for preventing, treating or inhibitingseizure disorders such as convulsions, epilepsy and status epilepticus.

In one embodiment, the compounds of the invention are considered usefulin the prevention, treatment and inhibition of convulsions.

In another embodiment, the compounds of the invention are considereduseful in the prevention, treatment and inhibition of epilepsy,epileptic syndromes and epileptic seizures.

In yet another embodiment, the compounds of the invention are considereduseful in the prevention, treatment and inhibition of anxiety disorderssuch as anxiety and conditions and diseases related to panic attack,agoraphobia, panic disorder with agoraphobia, panic disorder withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia and other specific phobias, obsessive-compulsivedisorder, posttraumatic stress disorder, acute stress disorders,generalized anxiety disorder, anxiety disorder due to general medicalcondition, substance-induced anxiety disorder, separation anxietydisorder, adjustment disorders, performance anxiety, hypochondriacaldisorders, anxiety disorder due to general medical condition andsubstance-induced anxiety disorder and anxiety disorder not otherwisespecified.

In yet another embodiment, the compounds of the invention are considereduseful in the prevention, treatment and inhibition of neuropathic painand migraine pain disorders such as allodynia, hyperalgesic pain,phantom pain, neuropathic pain related to diabetic neuropathy andneupathic pain related to migraine.

In yet another embodiment, t the compounds of the invention areconsidered useful in the prevention, treatment and inhibition ofneurodegenerative disorders such as Alzheimer's disease; Huntington'schorea; multiple sclerosis; amyotrophic lateral sclerosis;Creutzfeld-Jakob disease; Parkinson's disease; encephalopathies inducedby AIDS or infection by rubella viruses, herpes viruses, borrelia andunknown pathogens; trauma-induced neurodegenerations; neuronalhyperexcitation states such as in medicament withdrawal or intoxication;and neurodegenerative diseases of the peripheral nervous system such aspolyneuropathies and polyneuritides.

In yet another embodiment, the compounds of the invention are considereduseful in the prevention, treatment and inhibition of neurodegenerativedisorders such as Alzheimer's disease; Huntington's chorea; multiplesclerosis; amyotrophic lateral sclerosis; Creutzfeld-Jakob disease;Parkinson's disease; encephalopathies induced by AIDS or infection byrubella viruses, herpes viruses, borrelia and unknown pathogens; andtrauma-induced neurodegenerations.

In yet another embodiment, the compounds of the invention are considereduseful in the prevention, treatment and inhibition of neuronalhyperexcitation states such as in medicament withdrawal or intoxication.

The invention provides compounds showing effect in one or more of thefollowing tests:

-   -   “Relative efflux through the KCNQ2 channel”    -   Which is a measure of the potency of the compound at the target        channel    -   “Maximum electroshock”    -   Which is a measure of seizures induced by non-specific CNS        stimulation by electrical means    -   “Tilocarpine induced seizures”    -   Seizures induced by pilocarpine are often difficult to treat        with many existing antiseizure medications and so reflect a        model of “drug resistant seizures”    -   “Electrical seizure-threshold tests” and “Chemical        seizure-threshold tests”    -   These models measure the threshold at which seizures are        initiated, thus being models that detect whether compounds could        delay seizure initiation.    -   “Amygdala kindling”    -   Which is used as a measure of disease progression, as in normal        animals the seizures in this model get more severe as the animal        receives further stimulations.

According to one particular aspect of the invention, the compounds areKCNQ2 active with an EC₅₀ of less than 15000 nM such as less than 10000nM as measured by the test “Relative efflux through the KCNQ2 channel”which is described below.

According to one particular aspect of the invention, the compounds areKCNQ2 active with an EC₅₀ of less than 2000 nM such as less than 1500 nMas measured by the test “Relative efflux through the KCNQ2 channel”which is described below.

According to another particular aspect of the invention, the compoundsare KCNQ2 active with an EC₅₀ of less than 200 nM such as less than 150nM as measured by the test “Relative efflux through the KCNQ2 channel”which is described below.

According to another particular aspect of the invention, the compoundshave an ED₅₀ of less than 15 mg/kg in the test “Maximum electroshock”which is described below.

According to yet another particular aspect of the invention, thecompounds have an ED₅₀ of less than 5 mg/kg in the test “Maximumelectroshock” which is described below.

According to one particular aspect of the invention, the compounds havean ED₅₀ of less than 5 mg/kg in the “Electrical seizure-threshold test”and “Chemical seizure-threshold test” which is described below.

Some compounds have few or clinically insignificant side effects. Someof the compounds are thus tested in models of the unwanted sedative,hypothermic and ataxic actions of the compounds.

Some of the compounds have a large therapeutic index betweenanticonvulsant efficacy and side-effects such as impairment of locomotoractivity or ataxic effects as measured by performance on a rotating rod.This means that the compounds will expectedly be well tolerated inpatients permitting high doses to be used before side effects are seen.Thereby compliance with the therapy will expectedly be good andadministration of high doses may be permitted making the treatment moreefficacious in patients who would otherwise have side effects with othermedications.

Definitions

The term heteroatom refers to a nitrogen, oxygen or sulphur atom.

Halogen means fluoro, chloro, bromo or iodo.

The expressions C₁₋₆-alk(en/yn)yl and C₁₋₆-alk(an/en/yn)yl mean aC₁₋₆-alkyl, C₂₋₆-alkenyl or a C₂₋₆-alynyl group.

The term C₁₋₆-alkyl refers to a branched or un-branched alkyl grouphaving from one to six carbon atoms inclusive, including but not limitedto methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl and 2-methyl-1-propyl.

Similarly, C₂₋₆-alkenyl and C₂₋₆-alkynyl, respectively, designate suchgroups having from two to six carbon atoms, including one double bondand one triple bond respectively, including but not limited to ethenyl,propenyl, butenyl, ethynyl, propynyl and butynyl.

The expression C₁₋₃-alk(en/yn)yl means a C₁₋₃-alkyl, C₂₋₃-alkenyl or aC₂₋₃-alkynyl group.

The term C₁₋₃-alkyl refers to a branched or un-branched alkyl grouphaving from one to three carbon atoms inclusive, including but notlimited to methyl, ethyl, 1-propyl and 2-propyl.

Similarly, C₂₋₃-alkenyl and C₂₋₃-alkynyl, respectively, designate suchgroups having from two to three carbon atoms, including one double bondand one triple bond respectively, including but not limited to ethenyl,propenyl, ethynyl and propynyl.

The expressions C₃₋₈-cycloalk(en)yl and C₃₋₈-cycloalk(an/en)yl mean aC₃₋₈-cycloalkyl- or cycloalkenyl group.

The term C₃₋₈-cycloalkyl designates a monocyclic or bicyclic carbocyclehaving three to eight C-atoms, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, etc.

The expressions C₃₋₆-cycloalk(en)yl and C₃₋₆-cycloalk(an/en)yl mean aC₃₋₆-cycloalkyl- or cycloalkenyl group.

The term C₃₋₆-cycloalkyl designates a monocyclic or bicyclic carbocyclehaving three to six C-atoms, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, etc.

The term C₃₋₈-cycloalkenyl designates a monocyclic or bicycliccarbocycle having three to eight C-atoms and including one double bond.

The term heterocycloalk(en)yl designates monocyclic or bicyclic ringsystems wherein the ring is formed by 5 to 8 atoms being selected fromthe group consisting of carbon atoms and heteroatoms; with the provisothat one or two of the ring forming atoms are independently selectedheteroatoms. The term heterocycloalk(en)yl may thus designate amonocyclic or bicyclic ring system wherein the ring is formed by 5 to 8atoms selected from 3-7 carbon atoms and 1 or 2 heteroatoms selectedfrom N, S, or O. Examples of such ring systems are morpholine,pyrrolidine, piperidine and piperazine.

The term halo-C₁₋₆-alk(en/yn)yl designates C₁₋₆-alk(en/yn)yl beingsubstituted with one or more halogen atoms, including but not limited totrifluoromethyl. Similarly, halo-C₃₋₈-cycloalk(en)yl designatesC₃₋₈-cycloalk(en)yl being substituted with one or more halogen atoms andhalo-heterocycloalk(en)yl designates heterocycloalk(en)yl beingsubstituted with one or more halogen atoms.

The term NR¹⁰R^(10′)—C₁₋₆ alk(en/yn)yl designates C₁₋₆-alk(en/yn)ylbeing substituted with NR¹⁰R^(10′); NR¹²R^(12′)—C₁₋₆-alk(en/yn)yldesignates C₁₋₆-alk(en/yn)yl being substituted with NR¹²R^(12′); andNR⁷R^(7′)—C₁₋₆-alk(en/yn)yl designates C₁₋₆-alk(en/yn)yl beingsubstituted with NR⁷R^(7′). 2-amino-4-methyl-pentane is an example ofsuch group, the example is not intended to be construed as limiting.

The term NR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl designates C₃₋₈-cycloalk(en)ylbeing substituted with NR¹⁰R^(10′); NR¹²R^(12′)—C₃₋₈-cycloalk(en)yldesignates C₃₋₈-cycloalk(en)yl being substituted with NR¹²R^(12′); andNR⁷R^(7′)—C₃₋₈-cycloalk(en)yl designates C₃₋₈-cycloalk(en)yl beingsubstituted with NR⁷R^(7′). 1-amino-cyclopropane is an example of suchgroup, the example is not intended to be construed as limiting.

The term NR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl designatesC₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl being substituted withNR¹⁰R^(10′); NR¹²R^(12′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yldesignates C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl being substituted withNR¹²R^(12′); and NR⁷R^(7′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yldesignates C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl being substituted withNR⁷R^(7′).

When any of NR¹²R^(12′)—C₁₋₆-alk(en/yn)yl,NR¹²R^(12′)—C₃₋₈-cycloalk(en)yl,NR¹²R^(12′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl is optionallysubstituted, then any of C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl is optionally substituted with oneor more substituents independently being C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl or Ar.

As used herein, the term acyl refers to formyl,C₁₋₆-alk(en/yn)ylcarbonyl, C₃₋₈-cycloalk(en)ylcarbonyl, Ar-carbonyl,Ar—C₁₋₆-alk(en/yn)ylcarbonyl or aC₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl-carbonyl group, whereinC₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl and Ar are as defined above.

When two substituents together with a nitrogen atom form a 5-8 memberedsaturated or unsaturated ring which optionally contains one furtherheteroatom, then a monocyclic ring system is formed by 5 to 8 atoms, oneor two of said atoms are heteroatoms selected from N, S, or O. Examplesof such ring systems are pyrrolidine, piperidine, piperazine,morpholine, pyrrole, oxazolidine, thiazolidine, imidazolidine,azetidine, beta-lactame, tetrazole and pyrazole.

When two adjacent substituents together with an aromatic group to whichthey are attached form a 5-8 membered ring, which optionally containsone or two heteroatoms, then a ring is formed by 5-8 atoms selected from3-8 carbon atoms and 0-2 heteroatoms selected from N, S, or O and. Suchtwo adjacent substituents may together form:

-   —(CH₂)_(n″)—CH₂—, —CH═CH—(CH₂)_(m″)—, —CH₂—CH═CH—(CH₂)_(p″)—,    —CH═CH—CH═CH—, —(CH₂)_(n″)—O—, —O—(CH₂)_(m″)—O—,    —CH₂—O—(CH₂)_(p″)—O—, —CH₂—O—CH₂—O—CH₂—, —(CH₂)_(n″)—S—,    —S(CH₂)_(m″)—S—, —CH₂—S—(CH₂)_(p″)—S—, —CH₂—S—CH₂—S—CH₂—,    —(CH₂)_(n″)—NH—, —NH—(CH₂)_(m″)—NH—, —CH₂—NH—(CH₂)_(p″)—NH—,    —CH═CH—NH—, —O—(CH₂)_(m″)—NH—, —CH₂—O—(CH₂)_(p″)—NH— or    —O—(CH₂)_(p″)—NH—CH₂—, —S—(CH₂)_(m″)—NH—, —N═CH—NH—, —N═CH—O— or    —N═CH—S—, wherein m″ is 1, 2 or 3, n″ is 2, 3 or 4 and p″ is 1 or 2.

The term Ar refers to optionally substituted aromatic systems of 5-10carbon atoms, wherein 0, 1, 2, 3 or 4 carbon atoms may be replaced byheteroatoms independently selected from N, S, or O. Examples of such Argroups are optionally substituted phenyl, optionally substitutednaphtyl, optionally substituted quinoline, optionally substituted indol,optionally substituted pyridine, optionally substituted pyrimidine,optionally substituted thiophene, optionally substituted furan,optionally substituted thiazole and optionally substituted oxazole. Suchoptionally substituted Ar groups may be substituted with one or moresubstituents independently being hydroxy, halogen, C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)yloxy, C₃₋₈-alk(en/yn)yloxy,acyl, nitro, cyano, —CO—NH—C₁₋₆-alk(en/yn)yl, —CO—N(C₁₋₆-alk(en/yn)yl)₂,—NH₂, —NH—C₁₋₆-alk(en/yn)yl, —N(C₁₋₆-alk(en/yn)yl)₂,S—C₁₋₆-alk(en/yn)yl, —SO₂N(C₁₋₆-alk(en/yn)yl)₂ and—SO₂NH—C₁₋₆-alk(en/yn)yl, SO₂—C₁₋₆-alk(en/yn)yl andSO₂O—C₁₋₆-alk(en/yn)yl; or two adjacent substituents may together withthe aromatic group form a 5-8 membered ring, which optionally containsone or two heteroatoms and which may be saturated or unsaturated.

The terms C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,Ar—C₃₋₈-cycloalk(en)yl, Ar-heterocycloalk(en)yl,Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,Ar—C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,Ar—C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, C₁₋₆-alk(en/yn)yloxy,C₂₋₆-alkenyloxy, C₂₋₆-alkynyloxy, C₃₋₈-cycloalk(en)yloxy,C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yloxy-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-C₃₋₈-cycloalk(en)yl,C₁₋₆-alk(en/yn)yloxy-heterocycloalk(en)yl, Ar-oxy-C₁₋₆-alk(en/yn)yl,Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)ylcarbonyl,C₃₋₈-alk(en/yn)ylcarbonyl, Ar-carbonyl, Ar—C₁₋₆-alk(en/yn)ylcarbonyl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)ylcarbonyl, —CO—C₁₋₆-alk(en/yn)yl,S—C₁₋₆-alk(en/yn)yl, SO₂—C₁₋₆-alk(en/yn)yl and SO₂O—C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,acyl, acyl-C₁₋₆-alk(en/yn)yl, acyl-C₃₋₈-cycloalk(en)yl,acyl-heterocycloalk(en)yl, acyl-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,acyl-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,acyl-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, hydroxy-C₁₋₆-alk(en/yn)yl,hydroxy-C₃₋₈-cycloalk(en)yl, hydroxy-heterocycloalk(en)yl,hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,hydroxy-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,hydroxy-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₃₋₈-cycloalk(en)yl, halo-heterocycloalk(en)yl,halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,halo-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, halo-C₁₋₆-alk(en/yn)yl-Ar,halo-C₃₋₈-cycloalk(en)yl-Ar, halo-C₃₋₈-cycloalk(en)yl-C₁₋₆alk(en/yn)yl-Ar, halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl-Ar,halo-heterocycloalk(en)yl-Ar, cyano-C₁₋₆-alk(en/yn)yl,cyano-C₃₋₈-cycloalk(en)yl, cyano-heterocycloalk(en)yl,cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,cyano-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,cyano-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl etc. designate such groupsin which the C₁₋₆-alk(en/yn)yl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalk(en)yl, heterocycloalk(en)yl, Ar, cyano,halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,halo-heterocycloalk(en)yl and acyl are as defined above.

The salts of the invention are preferably pharmaceutically acceptablesalts. Such salts include pharmaceutically acceptable acid additionsalts, pharmaceutically acceptable metal salts, ammonium and alkylatedammonium salts.

The pharmaceutically acceptable salts of the invention are preferablyacid addition salts. The acid addition salts of the invention arepreferably pharmaceutically acceptable salts of the compounds of theinvention formed with non-toxic acids. Acid addition salts include saltsof inorganic acids as well as organic acids.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoricand nitric acids and the like. Such acid addition salts can be formed bymethods known to the person skilled in the art. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in J. Pharm. Sci.1977, 66, 2, which is incorporated herein by reference.

Representative examples of suitable organic acids include formic,acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic,citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic,oxalic, picric, pyruvic, salicylic, succinic, ethanesulfonic, tartaric,ascorbic, pamoic, gluconic, citraconic, aspartic, stearic, palmitic,EDTA, glycolic, p-aminobenzoic, glutamic, bis-methylenesalicylic,methanesulfonic, ethanedisulfonic, itaconic, benzenesulfonic,p-toluenesulfonic acids, theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline and the like.Further examples of pharmaceutical acceptable inorganic or organic acidaddition salts include the pharmaceutically acceptable salts listed inJ. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.

Examples of metal salts include lithium, sodium, potassium, magnesiumsalts and the like.

Examples of ammonium and alkylated ammonium salts include ammonium,methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-,n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and thelike.

Also intended as pharmaceutically acceptable acid addition salts are thehydrates, which the present compounds are able to form.

The compounds of the present invention may have one or more asymmetriccentres and it is intended that any optical isomers, as separated, pureor partially purified optical isomers or racemic mixtures thereof areincluded within the scope of the invention.

Furthermore, when a double bond or a fully or partially saturated ringsystem is present in the molecule geometric isomers may be formed. It isintended that any geometric isomers, as separated, pure or partiallypurified geometric isomers or mixtures thereof are included within thescope of the invention. Likewise, molecules having a bond withrestricted rotation may form geometric isomers. These are also intendedto be included within the scope of the present invention.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric formsthat the compounds are able to form are included within the scope of thepresent invention.

The compounds of this invention may exist in unsolvated as well as insolvated forms with solvents such as water, ethanol and the like. Ingeneral, the solvated forms are considered equivalent to the unsolvatedforms for the purposes of this invention.

Some of the compounds of the present invention contain chiral centresand such compounds exist in the form of isomers (i.e. enantiomers). Theinvention includes all such isomers and any mixtures thereof includingracemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic compounds of the present invention canalso be resolved into their optical antipodes, e.g. by fractionalcrystallization of d- or l- (tartrates, mandelates or camphorsulphonate)salts. The compounds of the present invention may also be resolved bythe formation of diastereomeric derivatives.

Additional methods for the resolution of optical isomers, known to thoseskilled in the art, may be used. Such methods include those discussed byJ. Jaques, A. Collet and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981).

Optically active compounds can also be prepared from optically activestarting materials.

The invention also encompasses prodrugs of the present compounds, whichon administration undergo chemical conversion by metabolic processesbefore becoming pharmacologically active substances. In general, suchprodrugs will be functional derivatives of the compounds of the generalformulas I, XXIX, XXX, XXXI, XXXII or XXXIII, which are readilyconvertible in vivo into the required compound of the formulas I, XXIX,XXX, XXXI, XXXII or XXXIII. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The invention also encompasses active metabolites of the presentcompounds.

Whenever mentioned in relation to the compounds of the formulas I, XXIX,XXX, XXXI, XXXII or XXXIII, the terms epilepsy and epilepsies embraceany of the epilepsies, epileptic syndromes and epileptic seizuresreferred to in International League Against Epilepsy: Proposal forrevised clinical and electroencephalographic classification of epilepticseizures. Commission on Classification and Terminology of theInternational League Against Epilepsy. Epilepsia 1981 22: 489-501 and inInternational League Against Epilepsy: Proposal for revisedclassification of epilepsies and epileptic syndromes. Commission onClassification and Terminology of the International League AgainstEpilepsy. Epilepsia 1939 30(4): 389-399.

Whenever mentioned in relation to the compounds of the formulas I, XXIX,XXX, XXXI, XXXII or XXXIII, the term anxiety disorders embracesconditions and diseases related to panic attack, agoraphobia, panicdisorder with agoraphobia, panic disorder without agoraphobia,agoraphobia without history of panic disorder, specific phobia, socialphobia, obsessive-compulsive disorder, posttraumatic stress disorder,acute stress disorders, generalized anxiety disorder, anxiety disorderdue to general medical condition, substance-induced anxiety disorder,separation anxiety disorder, adjustment disorders and anxiety disordernot otherwise specified as defined by American Psychiatric AssociationDiagnostic and statistical manual of mental disorders, 4ed 1994:110-113, 393-444 and 623-627.

Pharmaceutical Compositions

The compounds of this invention are generally utilized as the free baseor as a pharmaceutically acceptable salt thereof. Representativeexamples are mentioned above.

If desired, the pharmaceutical composition of the invention may comprisethe compound of formula I in combination with further pharmacologicallyactive substances such as those described in the foregoing.

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)route, the oral route being preferred. It will be appreciated that thepreferred route will depend on the general condition and age of thesubject to be treated, the nature of the condition to be treated and theactive ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosageforms such as capsules, tablets, dragees, pills, lozenges, powders andgranules. Where appropriate, they can be prepared with coatings such asenteric coatings or they can be formulated so as to provide controlledrelease of the active ingredient such as sustained or prolonged releaseaccording to methods well known in the art.

Liquid dosage forms for oral administration include solutions,emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Depotinjectable formulations are also contemplated as being within the scopeof the present invention.

Other suitable administration forms include suppositories, sprays,ointments, cremes, gels, inhalants, dermal patches, implants etc.

The pharmaceutical compositions of this invention or those which aremanufactured in accordance with this invention may be administered byany suitable route, for example orally in the form of tablets, capsules,powders, syrups, etc., or parenterally in the form of solutions forinjection. For preparing such compositions, methods well known in theart may be used, and any pharmaceutically acceptable carriers, diluents,excipients or other additives normally used in the art may be used.

A typical oral dosage is in the range of from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kgbody weight per day, and more preferred from about 0.05 to about 10mg/kg body weight per day administered in one or more dosages such as 1to 3 dosages. The exact dosage will depend upon the frequency and modeof administration, the sex, age, weight and general condition of thesubject treated, the nature and severity of the condition treated andany concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may conveniently be presented in unit dosage form bymethods known to those skilled in the art. A typical unit dosage formfor oral administration one or more times per day such as 1 to 3 timesper day may contain from 0.05 to about 1000 mg, preferably from about0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200mg.

For parenteral routes such as intravenous, intrathecal, intramuscularand similar administration, typically doses are in the order of abouthalf the dose employed for oral administration.

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. One exampleis a base addition salt of a compound having the utility of a free acid.When a compound of the invention contains a free acid such salts may beprepared in a conventional manner by treating a solution or suspensionof a free acid of the compound of the invention with a chemicalequivalent of a pharmaceutically acceptable base. Representativeexamples are mentioned above.

For parenteral administration, solutions of the novel compounds of theinvention in sterile aqueous solution, aqueous propylene glycol, aqueousvitamin E or sesame or peanut oil may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theaqueous solutions are particularly suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. Thesterile aqueous media employed are all readily available by standardtechniques known to those skilled in the art.

Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to a desiredvolume, sterilising the solution and filling it in suitable ampules orvials. Any suitable additive conventionally used in the art may beadded, such as tonicity agents, preservatives, antioxidants, etc.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solution and various organic solvents.

Examples of solid carriers are lactose, terra alba, sucrose,cyclodextrin, talc, agar, pectin, acacia, stearic acid and lower alkylethers of cellulose corn starch, potato starch, talcum, magnesiumstearate, gelatine, lactose, gums, and the like.

Any other adjuvants or additives usually used for such purposes such ascolourings, flavourings, preservatives etc. may be used provided thatthey are compatible with the active ingredients.

Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.Similarly, the carrier or diluent may include any sustained releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate, alone or mixed with a wax.

The pharmaceutical compositions formed by combining the novel compoundsof the invention and the pharmaceutical acceptable carriers are thenreadily administered in a variety of dosage forms suitable for thedisclosed routes of administration. The formulations may conveniently bepresented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, and whichmay include one or more suitable excipients. Furthermore, the orallyavailable formulations may be in the form of a powder or granules, asolution or suspension in an aqueous or non-aqueous liquid, or anoil-in-water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation maybe tablette, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge.

The amount of solid carrier will vary widely but will usually be fromabout 25 mg to about 1 g.

If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

If desired, the pharmaceutical composition of the invention may comprisethe compound of the formulae I, XXIX, XXX, XXXI, XXXII or XXXIII incombination with further pharmacologically active substances such asthose described in the foregoing.

Typical examples of recipes for the formulation of the invention are asfollows:

-   -   1) Tablets containing 5.0 mg of a compound of the invention        calculated as the free base:

Compound of formula I, XXIX, XXX, XXXI, 5.0 mg XXXII or XXXIII Lactose60 mg Maize starch 30 mg Hydroxypropylcellulose 2.4 mg Microcrystallinecellulose 19.2 mg Croscarmellose Sodium Type A 2.4 mg Magnesium stearate0.84 mg

-   -   2) Tablets containing 0.5 mg of a compound of the invention        calculated as the free base:

Compound of formula I, XXIX, XXX, XXXI, 0.5 mg XXXII or XXXIII Lactose46.9 mg Maize starch 23.5 mg Povidone 1.8 mg Microcrystalline cellulose14.4 mg Croscarmellose Sodium Type A 1.8 mg Magnesium stearate 0.63 mg

-   -   3) Syrup containing per milliliter:

Compound of formula I, XXIX, XXX, XXXI, 25 mg XXXII or XXXIII Sorbitol500 mg Hydroxypropylcellulose 15 mg Glycerol 50 mg Methyl-paraben 1 mgPropyl-paraben 0.1 mg Ethanol 0.005 mL Flavour 0.05 mg Saccharin sodium0.5 mg Water ad 1 mL

-   -   4) Solution for injection containing per milliliter:

Compound of formula I, XXIX, XXX, XXXI, 0.5 mg XXXII or XXXIII Sorbitol5.1 mg Acetic Acid 0.05 mg Saccharin sodium 0.5 mg Water ad 1 mLPreparation of the Compounds of the Invention

The compounds of the invention of the general formula I, wherein a, b,c, d, e, f, g, h, s, q, U, W, Z, R¹, R², R³, R⁵, R⁶, R^(6′), R⁷, R^(7′),R⁸, R⁹, R^(9′), R¹⁰, R¹¹, R¹² and R^(12′) are defined under formula Imay be prepared by the methods as described below and as represented inthe scheme.

Substituted 4-nitroanilines of the general formula IX or XI arecommercially available, described in the literature or preparedaccording to methods known to chemists skilled in the art. Inparticular, compounds of the general formula IX or XI with s being 0 andR² being substituted aryl or substituted heteroaryl as defined abovesuch as furanyl, thienyl, phenyl, pyridinyl can be prepared fromcorresponding compounds with R² being I or Br by means of cross-couplingreactions known to chemists skilled in the art, such as Suzuki coupling,Stille coupling, or other transition metal catalyzed cross-couplingreactions [D. W. Knight “Coupling Reactions Between sp2 Carbon Centers”in Comprehensive Organic Synthesis, v. 3, pp. 481-520, Pergamon Press1991]. Alternatively, 4-nitroanilines with the general formula IX or XIcan be prepared from the corresponding 2-substituted aniline in theprotected or unprotected form by nitration known to chemists skilled inthe art [R. Behnisch “Aromatische Nitro-Verbindungen” in Methoden derOrganische Chemie/(Houben-Weyl) p. 255, v. E16d, Thieme: 1992]. Inparticular, this method can be applied for compounds with the generalformula IX or XI where U is S, SO₂, or SO₂NR¹¹. Also, compounds of thegeneral formula IX or XI where U is S can be converted into compounds ofthe general formula IX or XI where U is SO₂ by oxidation according tomethods known to the chemist skilled in the art, for example byoxidation with 3-chloroperoxybenzoic acid or NaIO₄ in the presence ofRuCl₃ as a catalyst.

Compounds of the general formula XI are also prepared from compounds ofgeneral formula IX by the reaction with suitable electrophilic reagentsforming an R³-(Z)_(q)-X group, such as, but not limited to, alkyl, aryl,or heteroaryl chloroformiates or carbamoyl chlorides, carbonic acidanhydrides, acid fluorides, acid chlorides, acid bromides, acid iodides,activated esters, activated carbonic acids with activating reagents suchas carbodiimides, sulfonyl chlorides, or isocyanates in suitablesolvents, such as acetonitrile, tetrahydrofuran, 1,2-dichloroethane, ormethylene chloride, at a suitable temperature, such as room temperatureor reflux, achieved by conventional heating or under microwaveirradiation, with or without addition of bases, such magnesium oxide,potassium carbonate, sodium hydride, trialkylamines, sodium- orpotassium alcoholates, sodium or potassium carbonate, sodium orpotassium bicarbonate, or pyridine, reactions well known to the chemistskilled in the art.

Additionally, for further variation of R², compounds of the generalformula XI, wherein R² is methyl, U is oxygen, and s is 1, can bedemethylated by methods known to chemists skilled in the art, such astreatment with boron tribromide in a suitable solvent, such asdichloromethane, at a suitable temperature, such as 0° C. or roomtemperature. The resulting phenols can then be transformed intocompounds of the general formula XI, wherein U is oxygen, and s is 1, bymethods known to chemists skilled in the art. Such methods include: (a)the reaction with electrophiles, such as alkyl chlorides, alkylbromides, alkyl iodides, benzyl chlorides, benzyl bromides, benzyliodides, carbonic acid chlorides, carbonic acid bromides, or carbonicacid anhydrides in the presence of suitable bases, such as potassiumcarbonate, in a suitable solvent, such as tetrahydrofuran,N,N-dimethylformamide, or 1,2-dichloroethane, at suitable temperatures,such as room temperature or reflux temperature; (b) the reaction withalkyl, benzylic, or heteroarylalkyl alcohols under conditions known asthe Mitsunobu reaction (O. Mitsunobu Synthesis 1981, 1).

The nitro group in compounds of the general formula XI can be reducedwith suitable reducing agents such as zinc or iron powder in thepresence of acid such as acetic acid or aqueous hydrochloric acid, orhydrogen gas or ammonium formiate in the presence of suitablehydrogenation catalyst such as palladium on activated carbon in suitablesolvents such as methanol, ethanol, or tetrahydrofuran, at suitabletemperatures or under ultrasonic irradiation, to obtain anilines withthe general formula XII. Alternatively, tin (R) chloride or sodiumdithionite can be used as reducing agents under conditions well known tothe chemist skilled in the art.

Obtained anilines with the general formula XII are subjected toreductive alkylation reactions, known to chemists skilled in the art,with aldehydes of the general formula YCHO where Y is defined as abovein suitable solvents such as methanol, ethanol, xylene, tetrahydrofuran,acetonitrile, or mixtures thereof, at suitable temperatures with theformation of intermediate imines which can be reduced in situ or can beseparated by evaporation of the solvent or crystallisation. They arereduced to the compounds of the invention of the general formula I,where R¹ is hydrogen, with reducing agents, such as sodium borohydrateor sodium cyanoborohydrate, in a suitable solvent, such as ethanol,methanol or acetonitrile with or without addition of catalytic amountsof acid, such as acetic acid, at suitable temperatures.

Optionally, for variation of R¹, the obtained compounds of the generalformula I where R¹ is hydrogen can be further derivatized by the secondreductive alkylation procedure using suitable aldehydes and reducingagents such as sodium cyanoborohydrate, as described above. Thisprocedure can be performed in situ after the first reductive alkylationwith aldehydes of the general formula YCHO. Alternatively, R¹ can beintroduced by the electrophilic substitution reaction with theappropriate electrophiles of the general formula R¹-LG, where LG is asuitable leaving group such as iodide, bromide, or sulphonate underconditions known to the chemist skilled in the art.

For the further variation of R³, Z and X, the compounds of the inventionwith the general formula I can be obtained by an alternative route:

Compounds with the general formula XIII may be prepared by protection ofthe aniline nitrogen in the substituted 4-nitro anilines with thegeneral formula IX with an appropriate protecting group (PG¹)[Protective Groups in Organic Synthesis, 3rd Edition T. W. Greene, P. G.M. Wuts, Wiley Interscience 1999], such as a trifloroacetyl group knownto chemists skilled in the art as TFA group, by reaction with thereagent forming the protective group such as trifluoroacetic acidanhydride in a suitable solvent, such as 1,2-dichloroethane atappropriate temperatures.

Anilines with the general formula XIV are obtained by reduction of thenitro group according to methods known to chemists skilled in the art,as described above. Then they are subjected to the reductive alkylationreactions as described above, with the aldehydes of the general formulaYCHO to furnish compounds with the general formula XV.

Compounds with the general formula XV are subjected to the secondreductive alkylation step, as described above, to furnish compounds withthe general formula XVI, where PG¹ is TFA. Then the TFA group can beremoved by methods known to chemists skilled in the art, such ashydrolysis with aqueous potassium carbonate in an appropriate solvent,such as methanol, at a suitable temperature, furnishing compounds of thegeneral formula XVII.

The compounds of the invention with the general formula I where R¹ isnot hydrogen are obtained from anilines with the general formula XVII bythe reaction with suitable electrophilic reagents forming a R³-(Z)_(q)-Xgroup such as alkyl, aryl or heteroaryl chloroformiates or carbamoylchlorides, acid chlorides, acid bromides, acid iodides, sulfonylchlorides, isocyanates, carbonic acid anhydrides, activated carbonicacids with activating reagents such as carbodiimides or others as knownto chemists skilled in the art, in the suitable solvents, such asacetonitrile, tetrahydrofuran, 1,2-dichloroethane, or methylene chlorideat a suitable temperature, such as room temperature or reflux, with orwithout addition of bases, such as magnesium oxide, potassium carbonate,trialkylamines, or pyridine, or other methods as described above.

For the compounds of the invention with general formula I wherein R¹ ishydrogen, compounds with the general formula XV are subjected to theprotection with appropriate protective group (PG²), known to chemistsskilled in the art [Protective Groups in Organic Synthesis, 3rd EditionT. W. Greene, P. G. M. Wuts, Wiley Interscience 1999], to furnishcompounds with the general formula XVIII. In particular, compounds ofthe general formula XVIII where PG² is tert-butylcarbonyl group, knownto chemists skilled in the art as Boc group, can be prepared with theappropriate reagent forming protective group such as tert-butyl carbonicacid anhydride in an appropriate solvent such as acetonitrile and atappropriate temperature such as +80° C., to furnish compounds of thegeneral formula XVIII where PG² is Boc. Then the TFA protective group(PG¹) is removed, as described above, to furnish compounds with thegeneral formula XIX, followed by derivatisation with appropriateelectrophiles forming R³-(Z)_(q)-X group to furnish compounds with thegeneral formula XX, as described above.

Alternatively, compounds of the general formula XIX can be prepared from4-nitroanilines in three steps as follows: reductive alkylation ofcompounds of the general formula XXXIV as described above will furnishcompounds of the general formula XXXV, which can then be protected e.g.using di-tert-butyldicarbonate and dimethylaminopyridine in a suitablesolvent such as tetrahydrofuran, thus yielding compounds of the generalformula XXXVI, which can then be reduced to compounds of the generalformula XIX by an appropriate reducing agent such as Na₂S₂O₄ asdescribed above.

Finally, the compounds of the invention with general formula I whereinR¹ is hydrogen are obtained from the compounds with the general formulaX by means of deprotection of PG² by the methods known to chemistsskilled in the art. In particular, the Boc protective group can becleaved by the methods known to chemists skilled in the art such asdeprotection with an appropriate acid, for example trifluoroacetic acid,in the absence or presence of solvent such as methylene chloride ortoluene at appropriate temperatures.

Alternatively, compounds of the general formula I can be prepared by aroute as follows:

Compounds of the general formula XXI, wherein R², U, and s are asdefined above, are commercially available or prepared by methods knownto the chemist skilled in the art. These include the reactions of5-fluoro-2-nitrophenol under Mitsunobu-, alkylation- or acylationconditions as described above for the synthesis of compounds of thegeneral formula XI from phenols. Nucleophilic aromatic substitution withamines of the type Y—CH₂—NH—R¹, a reaction well known to chemistsskilled in the art, furnishes compounds with the general formula XXII.Alternatively, compounds with the general formula XXII can be preparedby reductive alkylation as described above of 4-nitroanilines of thegeneral formula XXXIV. Compounds with the general formula XXIII may beprepared by the reduction of the nitro group, carried out under theconditions as described above for the synthesis of compounds of thegeneral structures XII. The reaction of compounds with the the generalformula XXIII with suitable electrophilic reagents forming anR³-(Z)_(q)-X group, as described above for compounds of the generalformula XI, furnishes the compounds of the invention with the generalformula I.

Alternatively, compounds of the general formula I with s being 0 and R²being substituted aryl or substituted heteroaryl as defined above suchas furanyl, thienyl, phenyl, pyridinyl can be prepared from thecorresponding compounds with R² being I or Br by means of cross-couplingreactions, as described above.

EXAMPLES

Analytical LC-MSdata (LC-MS=LC/MS) were obtained on a PE Sciex API 150EXinstrument equipped with an APPI (atmospheric pressure photo ionisation)ion source and Shimadzu LC-8A/SLC-10A LC system. Column: 30×4.6 mmWaters Symmmetry C18 column with 3.5 μm particle size; Solventsystem:A=water/trifluoroacetic acid (100:0.05) andB=water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method: Lineargradient elution with 90% A to 100% B in 4 minutes and with a flow rateof 2 mL/minute. LC/MS-TOF (time-of-flight) data were obtained on amicromass LCT 4-ways MUX equipped with a Waters 2488/Sedex 754 detectorsystem. Column: 30×4.6 mm Waters Symmetry C18 column with 3.5 m particlesize; Solventsystem: A=water/trifluoroacetic acid (100:0.05) andB=water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method: Lineargradient elution with 90% A to 100% B in 4 minutes and with a flow rateof 2 mL/minute. The values for the found molecular ions (m/z, wherein mis the molecular ion mass and z is the charge) are assigned to themolecular mass (M), composed of the most abundant isotopes, optionallyplus or minus fragments. In the examples with [M+3]⁺ or [M+2]⁺assignments, the reported m/z values correspond to the highest peakselected from several molecular ion peaks with different isotopecomposition and the molecular mass M is calculated based on the mostabundant isotope distribution. Purity was determined by integration ofthe UV (254 nm) and ELSD trace. The retention times (RT) are expressedin minutes.

Preparative LC-MS-purification was performed on the same PE Sciex API150EX instrument. Column: 50×20 mm YMC ODS-A with 5 μm particle size;Method: Linear gradient elution with 80% A to 100% B in 7 minutes andwith a flow rate of 22.7 mL/minute. Fraction collection was performed bysplit-flow MS detection.

¹H NMR spectra were recorded at 500.13 MHz or at 250.13 MHz, both on aBruker Avance DRX500 or on a Bruker AC 250 instrument, respectively.Deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.8% D) wereused as solvents. TMS was used as internal reference standard. Chemicalshift values are expressed in ppm-values. The following abbreviationsare used for multiplicity of NMR signals: s=singlet, d=doublet,t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet,dt=double triplet, dq=double quartet, tt=triplet of triplets,m=multiplet and br. s=broad singlet, br. d=broad doublet, br. t=broadtriplet.

Preparation of Intermediates

N-(p-Fluorobenzyl)-methylamine was synthesised according to theprocedure described by G. M. Singer and A. W. Andrews J. Med. Chem.1983, 26, 309. 2-Iodo-4-nitroaniline was prepared according to theprocedure described by J. J. Pak, T. J. R. Weakley, and M. M Haley J.Amer. Chem. Soc. 1999, 121, 8182.

Preparation of Intermediates of the General Formula XI

(2-Chloro-4-nitrophenyl)-carbamic acid ethyl ester

A suspension of MgO (2.0 g), 2-chloro-4-nitroaniline (3.768 g, 21.83mmol) and ethyl chloroformate (5 mL) in acetonitrile (25 mL) was heatedto reflux temperature for 4 hours followed by addition of more ethylchloroformate (4 mL). The heating was continued until full conversion(20 hours) then the reaction mixture was filtered via a plug of SiO₂ (5g) with ethyl acetate as an eluent. Evaporation in vacuo (50° C.) gave5.8 g (100% yield) of crude title compound which was used in the nextstep without further purification. LC/MS (m/z) 245 ([M+H]⁺); RT=2.95,(UV, ELSD) 96%, 98.5%. ¹H NMR (DMSO-d₆): 1.27 (t, 3H), 4.19 (q, 2H),8.06 (d, 1H), 8.19 (dd, 1H), 8.30 (d, 1H), 9.49 (s, NH).

The following compounds were prepared analogously using appropriatechloroformates:

(2-Chloro-4-nitrophenyl)-carbamic acid propyl ester

Propyl chloroformate and tetrahydrofuran were used instead. The titlecompound was crystallized by addition of diisopropyl ether to the crudeproduct and separated by filtration. Yield 3.3 g (62%), colorless solid.¹H NMR (DMSO-d₆): 0.94 (t, 3H), 1.67 (m, 2H), 4.10 (t, 2H), 8.06 (d,1H), 8.20 (dd, 1H), 8.31 (d, 1H), 9.52 (s, NH).

(4-Nitrophenyl)-carbamic acid propyl ester

Reaction was performed at room temperature in acetone as a solvent. Theproduct was used in the next step without purification.

(4-Nitrophenyl)-carbamic acid ethyl ester

Reaction was performed at room temperature in acetone as a solvent. Theproduct was used in the next step without purification.

(2-Methoxy-4-nitrophenyl)-carbamic acid methyl ester

Reaction was performed at room temperature in acetone as a solvent. Theproduct was used in the next step without purification.

(2-Methoxy-4-nitrophenyl)-carbamic acid isopropyl ester

Reaction was performed at room temperature in acetone as a solvent. Theproduct was used in the next step without purification.

(2-Methoxy-4-nitrophenyl)-carbamic acid propyl ester

Reaction was performed at room temperature in acetone as a solvent. Theproduct was used in the next step without purification.

(2-Methoxy-4-nitrophenyl)-carbamic acid 4-fluorophenyl ester

Reaction was performed at room temperature in acetone as a solvent. Theproduct was used in the next step without purification.

(2-Methyl-4-nitrophenyl)-carbamic acid ethyl ester

The crude product was used in the next step without furtherpurification.

LC/MS (m/z) 207.9 ([M−16]⁺); RT=2.69, (UV, ELSD) 75%, 99.7%.

(2-Methyl-4-nitrophenyl)-carbamic acid propyl ester

The crude product was used in the next step without furtherpurification.

LC/MS (m/z) 223.1 ([M−15]⁺); RT=2.97, (UV, ELSD) 62%, 99.7%.

(2-Bromo-4-nitrophenyl)-carbamic acid propyl ester

The crude product was purified by crystallisation from ethylacetate-hexane. ¹H NMR (DMSO-d₆): 0.94 (t, 3H), 1.66 (m, 2H), 4.10 (t,2H), 7.97 (d, 1H), 8.23 (dd, 1H), 8.44 (d, 1H), 9.28 (br, s, NH).

(2-Iodo-4-nitrophenyl)-carbamic acid propyl ester

The crude product was purified by crystallisation from ethylacetate-hexane. Pale yellow needles. ¹H NMR (DMSO-d₆): 0.94 (t, 3H),1.66 (m, 2H), 4.09 (t, 2H), 7.79 (d, 1H), 8.24 (dd, 1H), 8.60 (d, 1H),9.07 (br. s, NH). LC/MS (m/z) 335.0 ([M-O]⁺); RT=3.40, (UV, ELSD) 99%,100%.

(4-Nitro-2-cyanophenyl)-carbamic acid propyl ester

Sodium hydride was used instead as a base prior to addition of propylchloroformate at room temperature. The crude product contaminated withdouble acylation product was treated with saturated aqueous sodiumbicarbonate (NaHCO₃) in methanol for 16 hours and purified by flashchromatography. ¹H NMR (CDCl₃): 1.01 (t, 3H), 1.76 (m, 2H), 4.22 (t,2H), 7.47 (br. s, 1H, NH), 8.43 (dd, 1H), 8.47 (d, 1H), 8.57 (d, 1H).

The following compounds were prepared analogously:

(4-Nitro-2-cyanophenyl)-carbamic acid ethyl ester

¹H NMR (DMSO-d₆): 1.28 (t, 3H), 4.21 (q, 2H), 7.88 (d, 1H), 8.47(dd,1H), 8.68 (d, 1H), 10.34 (s, 1H, NH). LC/MS (m/z) 220.1 ([M+H]⁺),RT=2.46, (UV, ELSD) 97%, 98%.

(2-Trifluoromethyl-4-nitrophenyl)-carbamic acid propyl ester

¹H NMR (CDCl₃): 1.00 (t, 3H), 1.75 (m, 2H), 4.20 (t, 2H), 7.26 (br. s,1H, NH), 8.41 (dd, 1H), 8.50 (d, 1H), 8.57 (d, 1H).

(2-Trifluoromethyl-4-nitrophenyl)-carbamic acid ethyl ester

¹H NMR (CDCl₃): 1.37 (t, 3H), 4.31 (q, 2H), 7.25 (br. s, 1H, NH), 8.41(dd, 1H), 8.50 (d, 1H), 8.57 (d, 1H).

N-(b 2-Methoxy-4-nitrophenyl)-butyramide

To a cold (ice/water bath) solution of 2-methoxy-4-nitroaniline (4.00 g,23.8 mmol) in acetonitrile (40 mL) and triethylamine (5 mL) butyrylchloride (2.66 g, 25 mmol) was added. After 30 minutes the obtainedsuspension was poured into saturated aqueous sodium bicarbonate (NaHCO₃)(300 mL). After sonication for 10 minutes the title compound wasseparated by filtration as a yellow-brown solid, washed with water anddried in vacuo. Yield 5.34 g, 94%. LC/MS (m/z) 238.9 ([M+H]⁺); RT=2.69,(UV, ELSD) 98%, 99%. ¹H NMR DMSO-d₆): 0.91 (t, 3H), 1.60 (m, 2H), 2.47(t, 2H), 3.98 (s, 3H, OMe), 7.79 (s, 1H), 7.88 (dd, 1H), 8.39 (d, 1H),9.50 (s, 1H, NH).

The following compound was prepared analagously using the appropriateacid chloride:

N-(2-Methoxy-4-nitrophenyl)-3,4-dichlorobenzamide

LC/MS (m/z) 313.0 ([M+H—NO]⁺; RT=3.72, (UV, ELSD) 99%, 100%. ¹H NMR(DMSO-d₆): 4.00 (s, 3H, OMe), 7.82 (d, 1H), 7.88 (d, 1H), 7.93 (m, 2H),8.17 (d, 1H), 8.20 (s, 1H), 10.01 (s, 1H, NH).

3,3-Dimethyl-N-(2-methyl-4-nitrophenyl)-butyramide

To a solution of 2-methyl-4-nitroaniline (5 g, 32.9 mmol) inacetonitrile (75 mL) tert-butylacetyl chloride (5.3 g, 1.2 eq.) wasadded. The obtained mixture was distributed into 15 Smith Process Vialsand sealed. Each vial was heated and stirred at 150° C. under microwaveirradiation for 10 minutes. The combined reaction mixture was evaporatedin vacuo to give 9.27 g of solid (100%) which was used in the next stepwithout further purification. LC/MS (m/z) 251.1 ([M+H]⁺); RT=3.01, (UV,ELSD) 89%, 99.6%. ¹H NMR (DMSO-d₆): 1.05 (s, 9H), 2.33 (s, 2H), 2.36 (s,3H), 7.91 (d, 1H), 8.05 (dd, 1H), 8.12 (d, 1H), 9.41 (s, 1H, NH).

The following compounds have been prepared analogously:

2,2-Dimethyl-N-(2-methyl-4-nitrophenyl)-propionamide

LC/MS (m/z) 237.1 ([M+H]⁺); RT=2.72, (UV, ELSD) 96.7%, 98.6%. ¹H NMR(DMSO-d₆): 1.26 (s, 9H), 2.31 (s, 3H), 7.61 (d, 1H), 8.05 (dd, 1H), 8.14(d, 1H), 9.06 (s, 1H, NH).

2-(4-Fluorophenyl)-N-(2-methyl-4-nitrophenyl)-acetamide

LC/MS (m/z) 288.9 ([M+H]⁺); RT=2.90, (UV, ELSD) 99.6%, 99.4%. ¹H NMR(DMSO-d₆): 2.34 (s, 3H), 3.79 (s, 2H), 7.18 (t, 2H), 7.39 (dd, 2H), 7.91(d, 1H), 8.06 (dd, 1H), 8.13 (d, 1H), 9.72 (s, 1H, NH).

2-(4-Fluorophenyl)-N-(2-iodo-4-nitrophenyl)-acetamide

The product was washed with ice-cold acetonitrile.

¹H NMR (DMSO-d₆): 3.81 (s, 2H), 7.16-7.19 (m, 2H), 7.41-7.44 (m, 2H),7.87 (d, 1H), 8.23 (dd, 1H), 8.62 (d, 1H), 9.66 (bs, 1H).

(2-Iodo-4-nitrophenyl)-carbamic acid ethyl ester

The product was purified by flash chromatography (silica, heptane/ethylacetate).

¹H NMR (DMSO-d₆): 1.27 (t, 3H), 4.18 (q, 2H), 7.80 (d, 1H), 8.24 (dd,1H), 8.60 (d, 1H), 9.05 (s, 1H).

(2-(Furan-2-yl)-4-nitrophenyl)-carbamic acid propyl ester

The mixture of (2-iodo-4-nitrophenyl)-carbamic acid propyl ester (30 mg,0.086 mmol), 0.9 M aqueous potassium carbonate (K₂CO₃) (0.285 mL, 0.257mmol), palladium (II) acetate (5 mg) and 2-furanboronic acid (48 mg,0.428 mmol) in acetone (2 mL) was heated to +125° C. for 3 minutes inthe sealed vial under microwave irradiation. The obtained reactionmixture was evaporated and the title compound was purified by flashchromatography on SiO₂ (5 g, gradient heptane-ethyl acetate). Yield 21mg, 84%. ¹H NMR (CDCl₃): 1.00 (t, 3H), 1.75 (m, 2H), 4.18 (t, 2H), 6.62(dd, 1H, furan), 6.79 (d, 1H, furan), 7.64 (d, 1H, furan), 8.16 (dd,1H), 8.36 (br. s, 1H, NH), 8.39 (d, 1H), 8.48 (d, 1H). LC/MS (m/z) 261.0([M+H]⁺); RT=1.57.

The following compound was prepared analogously with the appropriatedboronic acid:

(2-Phenyl-4-nitrophenyl)-carbamic acid propyl ester

The compound was used in the next step without purification.

(2-Methoxy-4-nitrophenylamine)-carbamic acid ethyl ester

2-Methoxy-4-nitrophenylamine (5.0 g) was dissolved in dry dioxane (30mL) and N,N-diisopropylethylamine (7.8 mL) was added at 0° C. Ethylchloroformate (4.25 mL) in dioxane (35 mL) was added dropwise, and theresulting mixture was allowed to warm to room temperature and stirredover night. Water (200 mL) was added and the mixture was extracted withethyl acetate (3×150 mL). The combined organic phase was washed withwater (2×200 mL) and brine (200 mL), dried over sodium sulfate,filtered, and evaporated in vacuo. The crude product was recrystallisedfrom ethanol to yield the title compound as colourless solid (4.45 g,62%).

¹H NMR (DMSO-d₆): 1.26 (t, 3H), 3.94 (s, 3H), 4.18 (q, 2H), 7.78 (d,1H), 7.90 (dd, 1H), 8.09 (d, 1H), 8.99 (s, 1H).

(2-Hydroxy-4-nitrophenyl)-carbamic acid ethyl ester

(2-Methoxy-4-nitrophenyl)-carbamic acid ethyl ester (2.15 g) wasdispensed in 1,2-dichloroethane (20 mL) and cooled to 0° C. Borontribromide (2.0 mL) in 1,2-dichloroethane (10 mL) was added dropwise.The reaction mixture was stirred 10 minutes at 0° C. and 30 minutes atroom temperature. The mixture was again cooled to 0° C., and water (10mL) was added carefully. The reaction mixture was neutralised withsaturated aqueous sodium bicarbonate and aqueous hydrochloric acid (5M).The resulting mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic phase was washed with water (2×100 mL) and brine (100mL), dried over magnesium sulfate, filtered, and evaporated in vacuo toyield the title compound as brownish solid (1.96 g, 97%).

¹H NMR (DMSO-d₆): 1.25 (t, 3H), 4.17 (q, 2H), 7.64 (d, 1H), 7.74 (dd,1H), 8.01 (d, 1H), 8.69 (s, 1H), 10.96 (br. s, 1H).

(2-Cyclopentyloxy-4-nitrophenyl)-carbamic acid ethyl ester

Cyclopentanol (7.24 mL, 376 mM in dry tetrahydrofuran) was added totriphenylphosphine (1.44 g, polystyrene bound, 1.89 mMol/g) under argon,followed by the addition of a solution of(2-Hydroxy-4-nitrophenyl)-carbamic acid ethyl ester (25.6 mL, 62 mM indry tetrahydrofuran) and a solution of diethylazodicarboxylate (7.24 mL,376 mM in dry tetrahydrofuran). The reaction mixture was shaken at roomtemperature over night. The resin was filtered and washed withtetrahydrofuran (THF) (35 mL) and methanol (35 mL). The combined organicphase was evaporated in vacuo. The crude product was purified by flashchromatography (silica gel, heptane/ethyl acetate, gradient) to yieldthe title compound as slightly yellow solid (294 mg, 64%).

¹H NMR (DMSO-d₆): 1.27 (t, 3H), 1.59 (m, 2H), 1.76 (m, 2H), 1.87 (m,2H), 1.94 (m, 2H), 4.19 (q, 2H), 5.01 (h, 1H), 7.72 (d, 1H), 7.86 (dd,1H), 8.11 (d, 1H), 8.82 (s, 1H).

The following compounds were prepared in an analogous fashion:

(4-Nitro-2-phenethyloxyphenyl)-carbamic acid ethyl ester

¹H NMR (DMSO-d₆): 1.28 (t, 3H), 3.15 (t, 2H), 4.19 (q, 2H), 4.38 (t,2H), 7.23 (t, 1H), 7.32 (t, 2H), 7.36 (d, 2H), 7.80 (d, 1H), 7.88 (dd,1H), 8.08 (d, 1H), 8.66 (s, 1H).

(2-Benzyloxy-4-nitrophenyl)-carbamic acid ethyl ester

¹H NMR (DMSO-d₆): 1.26 (t, 3H), 4.18 (q, 2H), 5.33 (s, 2H), 7.35 (t,1H), 7.41 (t, 2H), 7.55 (d, 2H), 7.86 (d, 1H), 7.89 (dd, 1H), 8.06 (d,1H), 8.95 (s, 1H).

(2-Isopropyloxy-4-nitrophenyl)-carbamic acid ethyl ester

¹H NMR (DMSO-d₆): 1.27 (t, 3H), 1.33 (d, 6H), 4.19 (q, 2H), 4.84 (h,1H), 7.78 (d, 1H), 7.86 (dd, 1H), 8.12 (d, 1H), 8.77 (s, 1H).

Preparation of Intermediates of the General Formula XII

(4-Amino-2-methyloxyphenyl)-carbamic acid ethyl ester

(2-Methoxy-4-nitrophenyl)-carbamic acid ethyl ester (2.20 g) wasdissolved in ethanol (220 mL). Aqueous hydrochloric acid (26 mL, 6 M)and iron powder (4.74 g) were added, and the mixture was stirred at 65°C. for 15 minutes. After cooling to room temperature, the mixture wasneutralised with saturated aqueous sodium bicarbonate and extracted withethyl acetate (3×200 mL). The organic phase was washed with water (2×100mL) and brine (100 mL), dried over magnesium sulfate, filtered, andevaporated in vacuo. The crude product was dissolved in ethanol (100mL), and the above procedure was repeated using aqueous hydrochloricacid (26 mL, 6M) and iron powder (3.7 g), to yield the title compound asa dark oil (1.80 g, 93%). ¹H NMR (DMSO-d₆): 1.19 (t, 3H), 3.67 (s, 3H),4.01 (q, 2H), 4.97 (s, 2H), 6.08 (dd, 1H), 6.23 (d, 1H), 6.97 (br. s,1H), 7.92 (br. s, 1H).

(4-Amino-2-iodophenyl)-carbamic acid ethyl ester

¹H NMR (CDCl₃): 1.31 (t, 3H), 3.58 (br. s, 2H), 4.21 (q, 2H), 6.52 (br.s, 1H), 6.67 (dd, 1H), 7.12 (d, 1H), 7.60 (br. d, 1H).

The following compound was prepared analogously:

N-(4-Amino-2-iodophenyl)-2-(4-fluorophenyl)-acetamide

¹H NMR (DMSO-d₆): 3.59 (br. s, 2H), 3.73 (s, 2H), 6.65 (dd, 1H), 7.05(d, 1H), 7.09-7.12 (m, 3H), 7.34-7.37 (m, 2H), 7.82 (d, 1H).

(4-Amino-2-chlorophenyl)-carbamic acid ethyl ester

To a cold (ice/water bath) vigorously stirred solution of crude(2-Chloro-4-nitrophenyl)-carbamic acid ethyl ester (5.8 g, 21.8 mmol) intetrahydrofuran (THF) (100 mL) and acetic acid (12 mL) zinc powder (20g) was added by small portions maintaining the temperature below 40° C.The mixture was allowed to warm slowly to room temperature and afterreaction completion (1 hour) it was filtered via a plug of SiO₂ (20 g)with ethyl acetate as an eluent. The obtained solution was evaporated invacuo and the crude yellow solid residue (4.9 g) was purified byprecipitation from tetrahydrofuran (THF)/heptane to give 3.00 g of thetitle compound as pale yellow solid, yield 56%. LC/MS (m/z) 214, 216(M⁺); RT=1.18, (UV, ELSD) 86%, 97%. ¹H NMR (DMSO-d₆): 1.18 (br. t, 3H),4.02 (q, 2H), 5.29 (s, 2H, NH₂), 6.45 (dd, 1H), 6.61 (d, 1H), 6.98 (br.d, 1H), 8.52 (br. s, NHCO).

The following compounds were prepared analogously:

(4-Amino-2-chlorophenyl)-carbamic acid propyl ester

Yield 84.6% (2.44 g, colorless solid). LC/MS (m/z) 228.1 (M⁺); RT=1.53,(UV, ELSD) 97.3%, 99%.

(4-Aminophenyl)-carbamic acid propyl ester

Purified by flash chromatography on SiO₂ (gradient heptane-ethylacetate). Dark purple crystalline solid, yield 3.066 g, 63.3%. LC/MS(m/z) 195 ([M+H]⁺); RT=1.18, (UV, ELSD) 87%, 98.3%.

(4-Aminophenyl)-carbamic acid ethyl ester

LC/MS (m/z) 180.8 ([M+H]⁺); RT=0.48, (UV, ELSD) 71%, 97%.

(4-Amino-2-methoxyphenyl)-carbamic acid methyl ester

LC/MS (m/z) 197.0 ([M+H]⁺); RT=0.49, (UV, ELSD) 71%, 98%.

(4-Amino-2-methoxyphenyl)-carbamic acid ethyl ester

LC/MS (m/z) 210.9 ([M+H]⁺); RT=0.98, (UV, ELSD) 69%, 97%.

(4-Amino-2-methoxyphenyl)-carbamic acid isopropyl ester

LC/MS (m/z) 224.0 (M⁺); RT=1.33, (UV, ELSD) 63%, 99%.

(4-Amino-2-methoxyphenyl)-carbamic acid propyl ester

LC/MS (m/z) 224.9 ([M+H]⁺); RT=1.36, (UV, ELSD) 70%, 98%.

(4-Amino-2-methoxyphenyl)-carbamic acid 4-fluorophenyl ester

LC/MS (m/z) 277.0 ([M+H]⁺); RT=1.64, (UV, ELSD) 44%, 93%.

(4-Amino-2-methylphenyl)-carbamic acid propyl ester

LC/MS (m/z) 208.1 (M⁺); RT=1.16, (UV, ELSD) 95%, 100%. ¹H NMR (CDCl₃):0.96 (t, 3H), 1.68 (m, 2H), 2.17 (s, 3H, Me), 3.59 (br. s, 2H, NH₂),4.09 (t, 2H), 6.14 (br. s, 1H, ArH), 6.51 (m, 2H), 7.32 (br. s, 1H, NH).

(4-Amino-2-methylphenyl)-carbamic acid ethyl ester

¹H NMR (CDCl₃): 1.28 (t, 3H), 2.16 (s, 3H, Me), 3.62 (br. s, 2H, NH₂),4.19 (q, 2H), 6.16 (br. s, 1H, ArH), 6.5 (m, 2H), 7.31 (br. s, 1H, NH).LC/MS (m/z) 195.1 ([M+H]⁺); RT=0.75, (UV, ELSD) 70%, 95%.

(4-Amino-2-trifluoromethylphenyl)-carbamic acid ethyl ester

¹H NMR (CDCl₃): 1.30 (t, 3H), 3.77 (br. s, 2H, NH₂), 4.20 (q, 2H), 6.52(br. s, 1H, ArH), 6.82 (dd, 1H), 6.87 (unres. d, 1H), 7.65 (br. s, 1H,NH).). LC/MS (m/z) 248.1 (M⁺); RT=1.65, (UV, ELSD) 94%, 90%.

(4-Amino-2-trifluoromethylphenyl)-carbamic acid propyl ester

¹H NMR (CDCl₃): 0.96 (t, 3H), 1.69 (m, 2H), 3.76 (br. s, 2H, NH₂), 4.11(t, 2H), 6.51 (br. s, 1H, ArH), 6.81 (dd, 1H), 6.87 (d, 1H), 7.61 (br.s, 1H, NH). LC/MS (m/z) 261.9 (M⁺); RT=2.06, (UV, ELSD) 92%, 98%.

(4-Amino-2-cyanophenyl)-carbamic acid ethyl ester

¹H NMR (DMSO-d₆): 1.21 (t, 3H), 4.07 (q, 2H), 5.49 (br. s, 2H, NH₂),6.81 (m, 2H, ArH), 7.04 (d, 1H), 9.09 (br. s, 1H, NH). LC/MS (m/z) 204.9(M⁺); RT 1.05, (UV, ELSD) 98%, 99%.

(4-Amino-2-cyanophenyl)-carbamic acid propyl ester

¹H NMR (CDCl₃): 0.98 (t, 3H), 1.71 (m, 2H), 3.72 (br. s, 2H, NH₂), 4.13(t, 2H), 6.81 (br. s, ArH), 6.82 (d, 1H), 6.89 (dd, 1H), 7.83 (br. s,1H, NH). LC/MS (m/z) 220.1 ([M+H]⁺); RT=1.52, (UV, ELSD) 98%, 100%.

N-(4-Amino-2-methoxyphenyl)-butyramide

LC/MS (m/z) 208.9 ([M+H]⁺); RT=0.77, (UV, ELSD) 81%, 95%. ¹H NMR(DMSO-d₆): 0.89 (t, 3H), 1.56 (m, 2H), 2.22 (t, 2H), 3.4 (very br. s,NH₂), 3.69 (s, 3H, OMe), 6.08 (dd, 1H), 6.25 (d, 1H), 7.27 (d, 1H), 8.62(s, 1H, NH).

N-(4-Amino-2-methoxyphenyl)-3,4-dichlorobenzamide

LC/MS (m/z) 311.2 (M⁺); RT=1.93, (UV, ELSD) 100%, 100%. ¹H NMR(DMSO-d₆): 3.70 (s, 3H, OMe), 5.12 (br. s, 2H, NH₂), 6.15 (dd, 1H), 6.30(d, 1H), 7.09 (d, 1H), 7.77 (d, 1H), 7.91 (dd, 1H), 8.17 (d, 1H), 9.46(s, 1H, NH).

N-(4-Amino-2-methylphenyl)-3,3-dimethylbutyramide

LC/MS (m/z) 221.1 ([M+H]⁺); RT=1.22, (UV, ELSD) 53.7%, 92.3%. ¹H NMR(DMSO-d₆): 1.02 (s, 9H), 2.02 (s, 3H), 2.11 (s, 2H), 4.89 (br. s, 2H,NH₂), 6.33 (dd, 1H), 6.38 (d, 1H), 6.82 (d, 1H), 8.83 (s, 1H, NH).

N-(4-Amino-2-methylphenyl)-2-(4-fluorophenyl)-acetamide

LC/MS (m/z) 259.1 ([M+H]⁺); RT=1.36, (UV, ELSD) 48.1%, 91.4%. ¹H NMR(DMSO-d₆): 1.95 (s, 3H), 3.56 (s, 2H), 4.88 (br. s, 2H, NH₂), 6.31 (dd,1H), 6.38 (d, 1H), 6.83 (d, 1H), 7.14 (t, 2H), 7.35 (dd, 2H), 9.16 (s,1H, NH).

N-(4-Amino-2-methylphenyl)-2,2-dimethylpropionamide

LC/MS (m/z) 206.9 ([M+H]⁺); RT=0.59, (UV, ELSD) 93%, 95%. ¹H NMR(DMSO-d₆): 1.19 (s, 9H), 1.98 (s, 2H), 4.87 (br. s, 2H, NH₂), 6.33 (dd,1H), 6.39 (d, 1H), 6.71 (d, 1H), 8.55 (s, 1H, NH).

[4-Amino-2-furan-2-yl)-phenyl]-carbamic acid propyl ester

¹H NMR (CDCl₃): 0.96 (t, 3H), 1.68 (m, 2H), 3.65 (br. s, 2H, NH₂), 4.10(t, 2H), 6.50 (dd, 1H, furan), 6.58 (d, 1H, furan), 6.66 (dd, 1H), 6.91(br. s (unresolved d), 1H), 7.26 (br. s, ArH), 7.52 (d, 1H), 7.72 (br.s, 1H, NH). LC/MS (m/z) 261.0 ([M+H]⁺); RT=1.57.

(2-Phenyl-4-aminophenyl)-carbamic acid propyl ester

LC/MS (m/z) 271.1 ([M+H]⁺); RT=1.75, (UV, ELSD) 57%, 99%.

(4-Amino-2-bromophenyl)-carbamic acid propyl ester

A suspension of iron powder (20 g, excess) and(2-Bromo-4-nitrophenyl)-carbamic acid propyl ester (2.183 g, 7.20 mmol)in ethanol (80 mL) and 6 M aqueous hydrochloric acid (20 mL) wassonicated at room temperature for 10 minutes. The mixture was slowlypoured into saturated aqueous sodium bicarbonate (NaHCO₃) solution,filtered and extracted with ethyl acetate. The combined organic solutionwas washed 3 times with saturated aqueous NaHCO₃, dried over sodiumsulfate (Na₂SO₄) and evaporated in vacuo to give 1.67 g of the titlecompound as pale yellow oil which solidified. Yield 85%. LC/MS (m/z)271.9, 273.8 (M⁺); RT=1.30, (UV, ELSD) 99%, 100%. ¹H NMR (DMSO-d₆): 0.90(br. s (unresolved t), 3H), 1.59 (br. s (unresolved m), 2H), 3.94 (t,2H), 5.31 (s, 2H, NH₂), 6.50 (dd, 1H), 6.80 (unresolved d, 1H), 6.96(br. d, 1H), 8.51 (br. s, NHCO).

The following compound was prepared analogously:

(4-Amino-2-iodophenyl)-carbamic acid propyl ester

¹H NMR (CDCl₃): 0.97 (t, 3H), 1.69 (m, 2H), 3.59 (br. s, 2H, NH₂), 4.11(t, 2H), 6.53 (br. s, 1H, ArH), 6.66 (dd, 1H), 7.11 (d, 1H), 7.61 (br.s, 1H, NH). LC/MS (m/z) 320.7 ([M+H]⁺); RT=1.71, (UV, ELSD) 98%, 99%.

Synthesis of Intermediates of the General Formulas XIII-XXIII:

N-(4-Amino-2-chlorophenyl)-2,2-trifluoroacetamide

To a suspension of 4-nitro-2-chloroaniline (17.2 g, 0.1 mol) in1,2-dichloroethane (100 mL) trifluoroacetic anhydride (16 mL, 0.113 mol)was added. Obtained yellow solution was evaporated in vacuo after 5minutes. The obtained yellow solid ofN-(4-nitro-2-chlorophenyl)-2,2,2-trifluoroacetamide was reduced with theZn-powder in tetrahydrofuran (THF)-acetic acid as described above. Theobtained crude product was treated with 2 M hydrochloric acid (150 mL)and diethyl ether. The obtained white precipitate was filtered to give14.7 g of the title product as hydrochloride salt. The aqueous solutionwas neutralized with saturated aqueous sodium bicarbonate (NaHCO₃) andfiltered to give 4.58 g of the pure title compound as a pale grey solid.¹H NMR (DMSO-d₆): 5.54 (br. s, 2H, NH₂), 6.53 (dd, 1H), 6.70 (d, 1H),7.02 (d, 1H), 10.79 (br. s, 1H, NHCO). LC/MS (m/z) 239.8 ([M+H]⁺);RT=1.67, (UV) 100%.

N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide

A solution of N-(4-Amino-2-chlorophenyl)-2,2,2-trifluoroacetamide (4.567g, 19.14 mmol) and 5-chloro-thiophene-2-carboxaldehyde (3.97 g, 27.1mmol) in anhydrous ethanol (50 mL) was heated to reflux for 15 minutesand evaporated in vacuo at 70° C. (0.1 mbar, 30 min). The obtained crudeimine as a crystalline solid was dissolved in methanol followed byaddition of sodium cyanoborohydride (NaBH₃CN) in methanol (50 mL) andacetic acid (9 mL) by portions. The obtained reaction mixture wasstirred at room temperature for 60 minutes and evaporated in vacuo tosmall volume. The concentrated solution was quenched with water andfiltered after 30 minutes to give 6.98 g (99% yield) of the titlecompound as a brown-yellow solid. ¹H NMR (DMSO-d₆): 4.43 (d, 2H), 6.63(dd, 1H), 6.77 (d, 1H), 6.79 (t, 1H, NH), 6.94 (d, 1H), 6.97 (d, 1H),7.10 (d, 1H), 10.85 (br. s, 1H, NHCO). LC/MS (m/z) 367.9 (M⁺); RT=3.36,(UV, ELSD) 99%, 100%.

N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]phenyl}-2,2,2-trifluoroacetamide

To a mixture ofN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide(3.28 g, 8.88 mmol), 37% aqueous formaldehyde (5 mL), and acetic acid (3mL), sodium cyanoborohydride (NaBH₃CN) (1.1 g) in methanol (10 mL) wasadded dropwise with stirring during 30 minutes. The reaction mixture wasallowed to stand at room temperature for 2 hours and poured into water.After the oil solidified, it was filtered, washed with water and driedin vacuo to give 3.26 g of pale yellow-brown solid. Yield 95%. ¹H NMR(DMSO-d₆): 2.97 (s, 3H, NMe), 4.72 (s, 2H), 6.82 (m, 1H), 6.91 (m, 2H),6.97 (d, 1H), 7.21 (d, 1H), 10.92 (br. s, 1H, NHCO). LC/MS (m/z) 382.0(M⁺); RT=3.66, (UV, ELSD) 85%, 98%.

(5-Chloro-thiophen-2-ylmethyl)-[3-chloro-4-(2,2,2-trifluoro-acetylamino)-phenyl]-carbamicacid tert-butyl ester

A mixture ofN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide(2.219 g, 6.01 mmol), di-tert-butyl dicarbonate (2 g), and acetonitrile(3 mL) was heated to +80° C. until reaction completion (36 hours).During this time additional amount of di-tert-butyl dicarbonate wasadded (2×1.5 g). The obtained reaction mixture was evaporated in vacuo(80° C., 0.1 mbar) to give the crude title compound which was used inthe next step without further purification. ¹H NMR DMSO-d₆): 1.44 (s,9H), 4.94 (s, 2H), 6.81 (d, 1H), 6.93 (d, 1H), 7.25 (dd, 1H), 7.43 (d,1H), 7.50 (d, 1H), 11.24 (br. s, 1H, NHCO). LC/MS (m/z) 366.9([M-Boc]⁺); RT=3.99, (UV, ELSD) 87%, 96%.

2-Chloro-N(4)-(5-chloro-thiophen-2-ylmethyl)-N(4)-methyl-benzene-1,4-diamine

To a solution ofN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2,2,2-trifluoroacetamide(3.118 g) in methanol (MeOH) (50 mL) solution of potassium carbonate(K₂CO₃) (6.4 g) in water (25 mL) was added and the reaction mixture wasstirred until reaction completion (24 hours) at room temperature. Theobtained reaction mixture was extracted with ethyl acetate, washed withsaturated aqueous sodium bicarbonate (NaHCO₃) and evaporated to give2.26 g of dark brown oil which was used in the next step without furtherpurification. ¹H NMR (DMSO-d₆): 2.71 (s, 3H, NMe), 4.47 (s, 2H), 4.71(br. s, 2H, NH₂), 6.67-6.75 (m, 3H), 6.82 (d, 1H), 6.93 (d, 1H). LC/MS(m/z) 288.0 ([M+H]⁺); RT=2.07, (UV, ELSD) 85%, 98%.

The following compound was prepared analogously:

(4-Amino-3-chlorophenyl)-(5-chloro-thiophen-2-ylmethyl)-carbamic acidtert-butyl ester

¹H NMR (DMSO-d₆): 1.39 (br. s, 9H, tert-Bu), 4.74 (s, 2H), 5.35 (br. s,2H, NH₂), 6.67-6.74 (m, 2H), 6.77 (br. d, 1H), 6.90 (d, 1H), 6.97 (d,1H). LC/MS (m/z) 271.9 ([M-Boc]⁺); RT=3.73, (UV, ELSD) 77%, 97%.

4-Fluoro-2-isopropoxy-1-nitrobenzene

5-Fluoro-2-nitrophenol (48 g) was dissolved in dry tetrahydrofuran (THF)(300 mL). Triphenylphosphine (88 g) and 2-propanol (47 mL) were added,and the resulting mixture was cooled to 0° C.Diisopropylazodicarboxylate (66 mL) was added dropwise. The resultingmixture was allowed to warm to room temperature and stirred over night.The solvent was evaporated in vacuo and the resulting mixture wasfiltered through silica (heptane/ethyl acetate 1:1). The solvent wasevaporated in vacuo and the resulting mixture was recrystallised fromheptane/ethyl acetate (1:1). The organic phase was separated from thecrystalline solid by filtration, the solvent was evaporated in vacuo,and the remaining product was purified by flash chromatography (silicagel, heptane/ethyl acetate 9:1), yielding the title compound ascolourless oil (47.2 g, 78%).

¹H NMR (DMSO-d₆): 1.30 (d, 6H), 4.85 (h, 1H), 6.93 (m, 1H), 7.34 (dd,1H), 7.96 (dd, 1H).

The following compounds were prepared analogously:

2-Cyclopentyloxy-4-fluoro-1-nitrobenzene

¹H NMR (DMSO-d₆): 1.57-1.78 (m, 6H), 1.86-1.94 (m, 2H), 6.90-6.97 (m,1H), 7.27-7.32 (m, 1H), 7.98 (dd, 1H).

2-Benzyloxy-4-fluoro-1-nitrobenzene

¹H NMR (DMSO-d₆): 5.33 (s, 2H), 6.96-7.04 (m, 1H), 7.32-7.49 (m, 6H),8.04 (dd, 1H).

(4-Fluorobenzyl)-(3-isopropoxy-4-nitrophenyl)-(methyl)-amine

4-Fluoro-2-isopropoxy-1-nitrobenzene (1.0 g) was dissolved in drydimethylsulfoxide (25 mL). Potassium carbonate (1.4 g) and(4-fluorobenzyl)-(methyl)-amine (0.84 g) were added. The resultingmixture was heated to 90° C. over night. After cooling to roomtemperature, water (75 mL) was added, and the resulting mixture wasextracted with ethyl acetate (3×75 mL). The organic phase was dried oversodium sulfate, filtered, and evaporated in vacuo to yield the titlecompound as slightly yellow solid (1.6 g, 100%).

LC-MS (m/z) 319.1 ([M+H]⁺); RT=3.43, (UV, ELSD) 85%, 96%.

¹H NMR (DMSO-d₆): 1.21 (d, 6H), 3.18 (s, 3H), 4.71 (m, 1H), 4.73 (s,2H), 6.26 (d, 1H), 6.41 (dd, 1H), 7.17 (m, 2H), 7.25 (m, 2H), 7.84 (d,1H).

The following compounds were prepared analogously:

(3-Benzyloxy-4-nitrophenyl) (4-fluorobenzyl)methylamine

LC-MS (m/z) 320.9 ([M+H-NO₂]⁺); RT=3.54, (UV, ELSD) 96%, 100%.

(3-Cyclopentyloxy-4-nitrophenyl)(4-fluorobenzyl)methylamine

LC-MS (m/z) 299.2 ([M+H-NO₂]⁺); RT=3.64, (UV, ELSD) 96%, 100%.

4-(4-Fluorobenzyl)-(methyl)-amino-2-isopropoxyaniline

(4-Fluorobenzyl)-(3-isopropoxy-4-nitrophenyl)-(methyl)-amine (1.60 g)was dissolved in methanol (50 mL). Ammonium formiate (1.91 g) andpalladium (10% on charcoal, 0.21 g) were added, and the mixture wasstirred for 1.5 hours at room temperature. The reaction mixture wasfiltered and the solvent was evaporated in vacuo. The residue wasdissolved in a small amount of methanol, and concentrated aqueous sodiumhydroxide (2 mL) was added. The resulting mixture was filtered through acolumn of silica gel (ethyl acetate as eluent). The resulting solutionwas evaporated in vacuo to yield crude title compound as a black oil(0.76 g), which was directly used in the next step.

LC-MS (m/z) 288.9 ([M+H]⁺); RT=1.91, (UV, ELSD) 80%, 72%.

(5-Chloro-thiophen-2-ylmethyl)-(methyl)-(3-methyl-4-nitrophenyl)-anine

A suspension of 5-chloro-thiophene-2-carbaldehyde (1.61 g, 11.0 mmol),3-methyl-4-nitroaniline (1.52 g, 10.0 mmol), and Amberlite IRC-84 (100mg, H⁺ form) in o-xylene (40 mL) was heated under nitrogen at 140° C.for 5 hour. After cooling to room temperature, the resin was removed byfiltration, and volatiles were evaporated. The residue was dissolved inacetonitrile (40 mL) and sodium cyanoborohydride (1.26 g, 20.0 mmol) wasadded in one portion, followed by acetic acid (1 mL) in several portionsover 15 minutes. Formaldehyde solution (37% in water, 2.23 mL, 30.0mmol) was then added and the mixture was stirred for a further 30minutes. Volatiles were evaporated and the residue partitioned betweensaturated aqueous sodium bicarbonate (100 mL) and ethyl acetate (100mL), and the aqueous phase was extracted with ethyl acetate (50 mL). Theorganic layers were dried over sodium sulfate, the solvent wasevaporated, and the residue analyzed by NMR. Incomplete N-methylationmandated the reductive amination step to be repeated three times (usingformaldehyde solution, 7.4 mL, 100 mmol, and sodium cyanoborohydride,2.07 g, 33 mmol) before complete conversion was attained. After this,the crude product was purified on a FlashMaster system (silica, elutedwith heptane/ethyl acetate mixtures) to yield the title compound as ayellow oil (1.85 g, 62%).

¹H NMR (CDCl₃): 2.64 (s, 3H), 3.11 (s, 3H), 4.66 (s, 3H), 6.52 (d, 1H),6.60 (dd, 1H), 6.69 (d, 1H), 6.77 (d, 1H), 8.10 (d, 1H).

N(4)-(5-Chloro-thiophen-2-ylmethyl)-2,N(4)-dimethyl-benzene-1,4-diamine

To a suspension of(5-chloro-thiophen-2-ylmethyl)-(methyl)-(3-methyl-4-nitrophenyl)-amine(1.85 g, 6.23 mmol) and iron powder (2.09 g, 37.4 mmol) in ethanol (60mL) was added 6 N HCl (12.5 mL, 75 mmol), and the mixture was stirredvigorously at +60° C. for 50 minutes. It was then poured into saturatedaqueous sodium bicarbonate (200 mL) to which enough sodium carbonate wasadded to attain a pH>10. The resulting mixture was extracted with ethylacetate (200 mL, then 2×100 mL), the extract was dried over sodiumsulfate and volatiles were evaporated. The residue was purified on aFlashMaster system (silica, eluted with heptane/ethyl acetate mixtures)to yield the title compound as a brown oil (1.51 g, 91%).

¹H NMR (CDCl₃): 2.16 (s, 3H), 2.79 (s, 3H), 3.32 (br. s, 2H), 4.39 (s,3H), 6.58-6.65 (m, 4H), 6.72 (d, 1H).

Synthesis of Intermediates of the General Formulas XXXV, XXXVI, and XIXfrom XXXIV:

(3-Methyl-4-nitrophenyl)-(4-trifluoromethylbenzyl)-amine

A suspension of 4-trifluoromethylbenzaldehyde (819 μL, 6.00 mmol),3-methyl-4-nitroaniline (609 mg, 4.00 mmol), and Amberlite IRC-84 (200mg, H⁺ form) in o-xylene (4 mL) was heated under nitrogen at 140° C. for6 hours. It was then cooled to room temperature, diluted with ethylacetate (5 mL), dried over sodium sulfate, filtered, and volatiles wereevaporated. The residue was dissolved in acetonitrile (20 mL) and sodiumcyanoborohydride (503 mg, 8.00 mmol) was added in one portion, followedby acetic acid (1 mL) in several portions over 15 minutes. After afurther 30 minutes solvents were evaporated and the residue waspartitioned between ethyl acetate (50 mL), brine (25 mL), and 10%aqueous potassium carbonate (25 mL). The organic layer was dried oversodium sulfate, solvents were evaporated, and the residue was purifiedon a FlashMaster system (silica, eluted with heptane/ethyl acetatemixtures) to yield the title compound as a yellow powder (1.02 g, 82%).

¹H NMR (CDCl₃): 2.59 (s, 3H), 4.50 (d, 2H), 4.76 (br. t, 1H), 6.40 (d,1H), 6.43 (dd, 1H), 7.45 (d, 2H), 7.63 (d, 2H), 8.05 (d, 1H).

(3-Methyl-4-nitrophenyl)-(4-trifluoromethylbenzyl)-carbamic acidtert-butyl ester

A solution of (3-methyl-4-nitrophenyl)-(4-trifluoromethylbenzyl)-amine(1.02 g, 3.29 mmol), di-tert-butyl dicarbonate (1.08 g, 4.93 mmol),dimethylaminopyridine (201 mg, 1.64 mmol), and triethylamine (687 μL,4.93 mmol) in acetonitrile (20 mL) was stirred at room temperature for18 hours in an open flask (to allow carbon dioxide to escape). Volatileswere evaporated and the residue was dissolved in ethyl acetate (50 mL).This solution was washed with sat. ammonium chloride (2×50 mL), driedover sodium sulfate, volatiles were evaporated, and the residue waspurified on a FlashMaster system (silica, eluted with heptane/ethylacetate mixtures) to yield the title compound as a pale yellow, viscousoil (1.17 g, 86%), which retained traces of heptane.

¹H NMR (CDCl₃): 1.44 (s, 9H), 2.58 (s, 3H), 4.95 (s, 2H), 7.16 (dd, 1H),7.21 (d, 1H), 7.34 (d, 2H), 7.60 (d, 2H), 7.96 (d, 1H).

(4-Amino-3-methylphenyl)-(4-trifluoromethylbenzyl)-carbamic acidtert-butyl ester

A solution of Na₂S₂O₄ (3.00 g, 17.2 mmol) in water (20 mL) was added toa solution of(3-methyl-4-nitrophenyl)-(4-trifluoromethylbenzyl)-carbamic acidtert-butyl ester (1.41 g, 3.44 mmol) in tetrahydrofuran (20 mL), and theresulting mixture was stirred for 20 hours at +55° C. After cooling toroom temperature, the water phase was saturated with potassiumcarbonate, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (2×20 mL). The combined organic layers weredried over sodium sulfate, solvents were evaporated, and the residue waspurified on a FlashMaster system (silica, eluted with heptane/ethylacetate mixtures) to yield the title compound as a white solid (1.09 g,83%).

¹H NMR (CDCl₃): 1.41 (s, 9H), 2.10 (s, 3H), 3.59 (br. s, 2H), 4.78 (s,2H), 6.56 (d, 1H), 6.76 (br. s, 2H), 7.36 (d, 2H), 7.55 (d, 2H).

Compounds of the Invention

Example 1 1a {4-[(Benzofuran-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid propyl ester

A mixture of 0.1 M solution of (4-amino-2-methylphenyl)-carbamic acidpropyl ester (0.35 mL, 0.035 mmol) and 0.1 M solution ofbenzofuran-2-carbaldehyde (0.35 mL) in tetrahydrofuran (THF) was kept at55° C. for 60 minutes. Volatiles were removed in vacuo. To the obtainedresidue 0.2 M sodium cyanoborohydride (NaBH₃CN) (0.5 mL) in methanol andacetic acid (0.03 mL) were added. After sonication for 60 minutes thereaction mixture was evaporated in vacuo and the title compound wasseparated by preparative LC/MS to give 5.1 mg of colorless solid. Yield43%. LC/MS (m/z) 339.2 ([M+H]⁺); RT=2.92, (UV, ELSD) 94%, 94%.

1b {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid ethyl ester

LC/MS (m/z) 323.9 (M⁺); RT=2.67, (UV, ELSD) 94%, 100%.

1c {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid ethyl ester

LC/MS (m/z) 340.0 (M⁺); RT=2.87, (UV, ELSD) 91%, 100%.

1d {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 365.3 ([M−H]⁺); RT=2.89, (UV, ELSD) 97%, 99%.

1e [4-(4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid ethylester

LC/MS (m/z) 326.0 (M⁺); RT=2.50, (UV, ELSD) 84%, 98%.

1f [4-(4-Fluoro-benzylamino)-2-methylphenyl]-carbamic acid propyl ester

LC/MS (m/z) 317.1 ([M+H]⁺); RT=2.32, (UV, ELSD) 82%, 96%.

1g(4-{[4-(4-Chloro-benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino}-2-methylphenyl)-carbamicacid propyl ester

LC/MS (m/z) 493.0 ([M+H]⁺); RT=3.18, (UV, ELSD) 91%, 97%.

1h {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid propyl ester

LC/MS (m/z) 317.1 ([M−H]⁺); RT=2.41, (UV, ELSD) 76%, 93%.

1i {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid propyl ester

LC/MS (m/z) 382.0 (M⁺); RT=2.96, (UV, ELSD) 70%, 87%.

1j {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid propyl ester

LC/MS (m/z) 338.2 (M⁺); RT=2.92, (UV, ELSD) 85%, 84%.

1k {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid propyl ester

LC/MS (m/z) 355.1 ([M+H]⁺); RT=3.08, (UV, ELSD) 93%, 97%.

1l {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 379.3 ([M−H]⁺); RT=3.08, (UV, ELSD) 91%, 95%.

1m [4-(4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid propylester

LC/MS (m/z) 341.2 ([M+H]⁺); RT=2.71, (UV, ELSD) 73%, 96%.

1o {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamicacid ethyl ester

LC/MS (m/z) 389.0 ([M+H]⁺); RT=3.24, (UV, ELSD) 98%, 99%.

1p {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamicacid ethyl ester

LC/MS (m/z) 345.0 ([M+H]⁺); RT=3.21, (UV, ELSD) 99%, 100%.

1q {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamicacid ethyl ester

LC/MS (m/z) 361.0 ([M+H]⁺); RT=3.28, (UV, ELSD) 95%, 100%.

1r [2-Chloro-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid ethylester

LC/MS (m/z) 346.0 (M⁺); RT=3.48, (UV, ELSD) 95%, 100%.

1s [2-Chloro-4-(4-fluoro-benzylamino)-phenyl]-carbamic acid propyl ester

LC/MS (m/z) 337.1 ([M+H]⁺); RT=3.20, (UV, ELSD) 97%, 99%.

1t2-Chloro-4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino}-phenyl)-carbamicacid propyl ester

LC/MS (m/z) 514.2 ([M+H]⁺); RT=3.52, (UV, ELSD) 94%, 99%.

1u {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamicacid propyl ester

LC/MS (m/z) 337.0 ([M−1]⁺); RT=3.27, (UV, ELSD) 94%, 100%.

1v {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamicacid propyl ester

LC/MS (m/z) 403.9 ([M+H]⁺); RT=3.45, (UV, ELSD) 99%, 99%.

1w {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 356.9 ([M−H]⁺); RT=3.43, (UV, ELSD) 98%, 95%.

1x {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamicacid propyl ester

LC/MS (m/z) 372.9 ([M−H]⁺); RT=3.49, (UV, ELSD) 93%, 99%.

1y {4-[(Benzofuran-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic acidpropyl ester

LC/MS (m/z) 357.1 ([M−H]⁺); RT=3.37, (UV, ELSD) 95%, 98%.

1z {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamicacid ethyl ester

LC/MS (m/z) 335.0 (M⁺); RT=2.91, (UV, ELSD) 99%, 100%.

1aa {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-carbamicacid methyl ester

LC/MS (m/z) 341.1 (M⁺); RT=2.62, (UV, ELSD) 96%, 100%.

1ab {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-carbamicacid isopropyl ester

LC/MS (m/z) 400.0 (M⁺); RT=2.93, (UV, ELSD) 96%, 100%.

1ac {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acidpropyl ester

LC/MS (m/z) 367.9 (M⁺); RT=2.66, (UV, ELSD) 87.0%, 95.0%.

1ad {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acidpropyl ester

LC/MS (m/z) 324.0 (M⁺); RT=2.60, (UV, ELSD) 88.2%, 96.5%.

1ae [2-Cyano-4-(4-isopropylbenzylamino)-phenyl]-carbamic acid ethylester

LC/MS (m/z) 337.0 (M⁺); RT=3.25, (UV, ELSD) 90.8%, 99.6%.

1af [2-Iodo-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid propylester

LC/MS (m/z) 452.0 (M⁺); RT=3.72, (UV, ELSD) 88.0%, 97.7%.

1ag [4-(4-tert-Butyl-benzylamino)-2-iodophenyl]-carbamic acid propylester

LC/MS (m/z) 465.9 ([M−1]⁺); RT=3.85, (UV, ELSD) 86.6%, 96.6%.

1ah [2-Iodo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acidpropyl ester

LC/MS (m/z) 479.0 ([M+H]⁺); RT=3.54, (UV, ELSD) 97.7%, 99.8%.

1ai [2-Iodo-4-(4-methylsulfanyl-benzylamino)-phenyl]-carbamic acidpropyl ester

LC/MS (m/z) 454.8 ([M−1]⁺); RT=3.38, (UV, ELSD) 98.0%, 99.8%.

1aj {2-Iodo-4-[4-(4-methylpiperazin-1-yl)-benzylamino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 508.9 ([M+H]⁺); RT=1.90, (UV, ELSD) 62.0%, 79.2%.

1ak{4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 421.9 (M⁺); RT=3.27, (UV, ELSD) 98.7%, 98.5%.

1al{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 378.0 (M⁺); RT=3.25, (UV, ELSD) 97.7%, 99.5%.

1am [4-(4-tert-Butyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamicacid ethyl ester

LC/MS (m/z) 394.2 (M⁺); RT=3.70, (UV, ELSD) 90.2%, 97.9%.

1an [4-(4-Methylsulfanyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamicacid ethyl ester

LC/MS (m/z) 384.1 (M⁺); RT=3.22, (UV, ELSD) 84.4%, 94.6%.

1ao{4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 438.1 ([M+H]⁺); RT=3.47, (UV, ELSD) 98.9%, 99.9%.

1ap [4-(4-Isopropylbenzylamino)-2-trifluoromethyl-phenyl]-carbamic acidpropyl ester

LC/MS (m/z) 393.3 ([M−1]⁺); RT=3.60, (UV, ELSD) 71.3%, 74.1%.

1aq [4-(4-tert-Butyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamicacid propyl ester

LC/MS (m/z) 408.3 (M⁺); RT=3.89, (UV, ELSD) 91.1%, 98.6%.

1ar[2-Trifluoromethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamicacid propyl ester

LC/MS (m/z) 421.1 ([M+H]⁺); RT=3.52, (UV, ELSD) 99.2%, 99.8%.

1as [4-(4-Dimethylamino-benzylamino)-2-trifluoromethyl-phenyl]-carbamicacid propyl ester

LC/MS (m/z) 394.3 ([M−1]⁺); RT=2.02, (UV, ELSD) 63.4%, 100.0%.

1at [4-(4-Methylsulfanyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamicacid propyl ester

LC/MS (m/z) 398.1 (M⁺); RT=3.40, (UV, ELSD) 92.5%, 98.1%.

1au {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamicacid propyl ester

LC/MS (m/z) 394.0 ([M+H]⁺); RT 3.15, UV, ELSD) 97.5%, 89.8%.

1av {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamicacid propyl ester

LC/MS (m/z) 348.9 (M⁺); RT=3.11, (UV, ELSD) 99.7%, 96.3%.

1aw [2-Cyano-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acidpropyl ester

LC/MS (m/z) 378.3 ([M+H]⁺); RT=3.25, (UV, ELSD) 99.6%, 99.7%.

1ax {2-Bromo-4[(5-bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 447.9 ([M+H]⁺); RT=3.48, (UV, ELSD) 99.3%, 99.3%.

1ay {2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 402.9 ([M+H]⁺); RT=3.47, (UV, ELSD) 95.7%, 99.6%.

1az [2-Bromo-4-(4-isopropylbenzylamino)-phenyl]-carbamic acid propylester

LC/MS (m/z) 406.1 ([M+H]⁺); RT=3.72, (UV, ELSD) 80.2%, 93.9%.

1ba [2-Bromo-4-(4-tert-butyl-benzylamino)-phenyl]-carbamic acid propylester

LC/MS (m/z) 418.2 (M⁺); RT=3.86, (UV, ELSD) 87.2%, 96.8%.

1bb [2-Bromo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acidpropyl ester

LC/MS (m/z) 431.0 ([M+H]⁺); RT 3.55, (UV, ELSD) 95.9%, 99.8%.

1bc [2-Bromo-4-(4-methylsulfanyl-benzylamino)-phenyl]-carbamic acidpropyl ester

LC/MS (m/z) 409.0 ([M+H]⁺); RT=3.36, (UV, ELSD) 98.4%, 99.7%.

1bdN-{4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-butyramide

LC/MS (m/z) 382.0+; RT=2.66, (UV, ELSD) 95.9%, 99.3%.

1beN-{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-butyramide

LC/MS (m/z) 339.2 ([M+H]⁺); RT=2.61, (UV, ELSD) 96.4%, 98.4%.

1bf N-[4-(4-Isopropylbenzylamino)-2-methoxyphenyl]-butyramide

LC/MS (m/z) 341.1 ([M+H]⁺); RT=2.49, (UV, ELSD) 91.1%, 100.0%.

1bg N-[4-(4-tert-Butyl-benzylamino)-2-methoxyphenyl]-butyramide

LC/MS (m/z) 355.2 ([M+H]⁺); RT=2.65, (UV, ELSD) 97.0%, 100.0%.

1bh N-[2-Methoxy-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide

LC/MS (m/z) 367.2 ([M+H]⁺); RT=2.79, (UV, ELSD) 93.9%, 96.6%.

1bi{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-furan-2-yl-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 390.1 (M⁺); RT=3.38, (UV, ELSD) 92.9%, 99.8%.

1bj [2-Furan-2-yl-4-(4-isopropylbenzylamino)-phenyl]-carbamic acidpropyl ester

LC/MS (m/z) 393.2 ([M+H]⁺); RT=3.41, (UV, ELSD) 89.9%, 100.0%.

1bk [5-(4-Fluorobenzylamino)-biphenyl-2-yl]-carbamic acid propyl ester

LC/MS (m/z) 379.3 ([M+H]⁺); RT=3.06, UV, ELSD) 83.7%, 99.7%.

1bl {5-[(5-Chloro-thiophen-2-ylmethyl)-amino]-biphenyl-2-yl}-carbamicacid propyl ester

LC/MS (m/z) 400.0 (M⁺); RT=3.48, (UV, ELSD) 89.8%, 98.7%.

1bm [5-(4-Isopropylbenzylamino)-biphenyl-2-yl]-carbamic acid propylester

LC/MS (m/z) 403.2 ([M+H]⁺); RT=3.37, (UV, ELSD) 73.8%, 98.7%.

1zzN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide

Data for this compound are reported above in the synthesis ofintermediates of the general formulas XII-XXIII

Example 2 2a{4-[(4-Fluoro-benzyl)-(methyl)amino]-2-methoxyphenyl}-carbamic acidpropyl ester

A mixture of (4-Amino-2-methoxyphenyl)-carbamic acid propyl ester (0.3mL, 0.1 M solution in tetrahydrofuran (THF)) and 4-fluorobenzaldehyde(0.3 mL, 0.1 M solution in tetrahydrofuran (THF)) was heated to 50° C.for 60 minutes and evaporated in vacuo. To the obtained residue, sodiumcyanoborohydride (NaBH₃CN) (0.6 mL, 0.2 M solution in methanol) andacetic acid (0.03 mL) were added. The reaction mixture was kept at roomtemperature for 30 minutes, then formaldehyde (0.03 mL, 37% in water)and acetic acid (0.03 mL) were added. After 30 minutes the reactionmixture was evaporated in vacuo. The title compound was separated bypreparative LC/MS to give 4.3 mg of colorless solid, yield 41%. ¹H NMR(1:4 DMSO-H₆/DMSO-D₆): 8.04 (br. s, NH), 7.25 (m, 2H), 7.13 (m, 3H),6.36 (s, 1H), 6.24 (d, 1H), 4.53 (s, 2H, CH₂), 3.93 (t, 2H), 3.70 (s,3H, OMe), 2.97 (s, NMe), 1.57 (m, 2H), 0.89 (t, 3H). LC/MS (m/z) 347.2([M+H]⁺); RT=2.32, (UV, ELSD) 96%, 100%.

The following compounds were prepared analogously from appropriateanilines and aldehydes:

2b[4-(Benzo[b]thiophen-2-ylmethyl-(methyl)amino)-2-methoxy-phenyl]-carbamicacid propyl ester

¹H NMR (1:4 DMSO-H₆/DMSO-D₆): 8.07 (br. s, NH), 7.86 (d, 1H), 7.76 (d,1H), 7.30 (m, 4H), 6.49 (s, 1H), 6.36 (d, 1H), 4.83 (s, 2H, CH₂), 3.94(t, 2H), 3.75 (s, 3H, OMe), 2.98 (s, NMe), 1.58 (m, 2H), 0.89 (t, 3H).).LC/MS (m/z) 385.0 ([M+H]⁺); RT=3.25, (UV, ELSD) 99%, 100%.

2c{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methoxy-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 367.9 (M⁺); RT=3.07, (UV, ELSD) 99%, 100%.

2d{4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-methoxy-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 412.1 (M⁺); RT=3.12, (UV, ELSD) 99%, 100%.

2e{2-Methoxy-4-[methyl-(5-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 348.0 (M⁺); RT=2.46, (UV, ELSD) 95%, 100%.

2f{4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-carbamicacid propyl ester

LC/MS (m/z) 398.0 ([M+2]⁺); RT=3.10, (UV, ELSD) 97.0%, 98.1%.

2g {4-[(4-Isopropylbenzyl)-(methyl)amino]-2-methylphenyl}-carbamic acidpropyl ester

LC/MS (m/z) 355.2 ([M+H]⁺); RT=2.70, (UV, ELSD) 85.4%, 99.5%.

2h{2-Methyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 380.3 (M⁺); RT=3.18, (UV, ELSD) 95.2%, 98.5%.

2i {2-Methyl-4-[methyl-(4-methylsulfanyl-benzyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 358.0 (M⁺); RT=2.42, (UV, ELSD) 97.9%, 99.0%.

2j {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-chlorophenyl}-carbamicacid ethyl ester

LC/MS (m/z) 374.9 ([M+H]⁺); RT=3.92, (UV, ELSD) 97.8%, 100.0%.

2k{2-Chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 387.3 ([M+H]⁺); RT=3.59, (UV, ELSD) 99.9%, 100.0%.

2l {2-Chloro-4-[methyl-(4-methylsulfanyl-benzyl)-amino]-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 363.1 ([M−1]⁺); RT=3.36, (UV, ELSD) 92.1%, 99.6%.

2m{4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-chlorophenyl}-carbamicacid propyl ester

LC/MS (m/z) 418.1 ([M+H]⁺); RT=3.80, (UV, ELSD) 99.3%, 100.0%.

2n{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 374.0 ([M+H]⁺); RT=3.77, (UV, ELSD) 99.6%, 99.9%.

2o {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-chlorophenyl}-carbamicacid propyl ester

LC/MS (m/z) 389.2 ([M+H]⁺); RT=4.09, (UV, ELSD) 99.6%, 99.9%.

2p {2-Chloro-4-[methyl-(4-trifluoroethyl-benzyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 401.1 ([M+H]⁺); RT=3.81, (UV, ELSD) 99.8%, 100.0%.

2q{4-[(5-Bromo-thiophene-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 435.9 ([M−1]⁺); RT=3.56, (UV, ELSD) 99.4%, 100.0%.

2r{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 392.3 (M⁺); RT=3.56, (UV, ELSD) 99.0%, 100.0%.

2s{4-[(4-Isopropyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 395.3 ([M+H]⁺); RT=3.85, (UV, ELSD) 99.0%, 100.0%.

2t{4-[(4-tert-Butyl-benzyl)-(ethyl)amino]-2-trifluoromethyl-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 409.2 ([M+H]⁺); RT=3.98, (UV, ELSD) 97.9%, 99.8%.

2u{4-[Methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 421.2 ([M+H]⁺); RT=3.59, (UV, ELSD) 92.9%, 98.5%.

2v{4-[Methyl-(4-methylsulfanyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamicacid ethyl ester

LC/MS (m/z) 397.0 ([M−1]⁺); RT=3.48, (UV, ELSD) 99.4%, 99.9%.

2w{4-[(5-Bromo-thiophen-2-ylmethyl)-methyl-amino]-2-trifluoromethyl-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 449.9 ([M−1]⁺); RT=3.76, (UV, ELSD) 99.5%, 100.0%.

2x{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 405.9 (M⁺); RT=3.73, (UV, ELSD) 98.4%, 100.0%.

2y{4-[(4-Isopropyl-benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 409.2 ([M+H]⁺); RT=4.04, (UV, ELSD) 99.3%, 99.9%.

2z{4[(4-tert-Butyl-benzyl)-methyl)amino]-2-trifluoromethyl-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 423.1 ([M+H]⁺); RT=4.29, (UV, ELSD) 98.9%, 99.7%.

2aa{4-[Methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 435.3 ([M+H]⁺); RT=3.77, (UV, ELSD) 99.7%, 99.9%.

2ab{4-[Methyl-(4-methylsulfanyl-benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 412.0 (M⁺); RT=3.67, (UV, ELSD) 99.3%, 99.8%.

2ac{4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-cyanophenyl}-carbamicacid propyl ester

LC/MS (m/z) 407.0 (M⁺); RT=3.39, (UV, ELSD) 97.7%, 99.6%.

2ad {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-cyanophenyl}-carbamicacid propyl ester

LC/MS (m/z) 380.3 ([M+H]⁺); RT=3.83, (UV, ELSD) 99.4%, 99.9%.

2ae{2-Cyano-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 392.3 ([M+H]⁺); RT=3.44, (UV, ELSD) 98.9%, 99.9%.

2af{2-Bromo-4-[(5-bromo-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 462.1 ([M+H]⁺); RT=3.84, (UV, ELSD) 98.2%, 99.9%.

2ag{2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 418.1 ([M+H]⁺); RT=3.83, (UV, ELSD) 99.3%, 100.0%.

2ah {2-Bromo-4-[(4-isopropylbenzyl)-(methyl)amino]-phenyl}-carbamic acidpropyl ester

LC/MS (m/z) 420.2 ([M+H]⁺); RT=4.04, (UV, ELSD) 98.8%, 99.7%.

2ai {2-Bromo-4-[(4-tert-butyl-benzyl)-(methyl)amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 432.1 (M⁺); RT=4.15, (UV, ELSD) 99.3%, 100.0%.

2aj{2-Bromo-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamicacid propyl ester

LC/MS (m/z) 447.0 ([M+H]⁺); RT=3.84, (UV, ELSD) 98.4%, 99.9%.

2zzN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2,2,2-trifluoroacetamide

Data for this compound are reported above in the synthesis ofintermediates of the general formula XIII-XXIII

Example 3 3a{4-[(4-Fluorobenzyl)-(methyl)-amino]-2-isopropoxyphenyl}-carbamic acidethyl ester

4-(4-Fluorobenzyl)-(methyl)-amino-2-isopropoxyaniline (0.29 g) wasdissolved in dry dioxane (3 mL). N,N-Diisopropylethylamine (0.27 mL) andethyl chloroformate (0.15 mL) were added, and the reaction mixture wasstirred at room temperature over night. Water (5 mL) was added, and theresulting mixture was extracted with ethyl acetate (3×10 mL). Theorganic phase was dried over sodium sulfate and filtered. The solventwas evaporated in vacuo, and the crude product was purified by flashchromatography (silica gel, heptane/ethyl acetate 19:1, 1%triethylamine, gradient). Evaporation of the solvent in vacuo furnishedthe title compound (0.20 g, 55%) as a colourless oil. LC-MS (m/z) 361.3([M+H]⁺); RT=2.58, (UV, ELSD) 90%, 98%.

Example 4 4a [4-(3-Fluorobenzylamino)-2-methoxyphenyl]-carbamic acidethyl ester

A solution of 3-fluorobenzaldehyde in dry methanol (84 μL, 476 mM) wasadded to a solution of (4-Amino-2-methyloxyphenyl)-carbamic acid ethylester (84 μL, 0.476 M in dry methanol). The resulting mixture was heatedto 40° C. for 30 minutes. The solvent was evaporated in vacuo, and theremaining material was dissolved in 1,2-dichloroethane (1 mL). Sodiumtriacetoxyborohydrate (20 mg) was added, and the resulting mixture waskept at room temperature for 2 hours, under 2 periods of sonication for10 minutes, respectively. The reaction mixture was filtered throughsilica gel (500 mg), and the column was washed with 1,2-dichloroethane(3 mL). The solvent was evaporated in vacuo yielding the title compound(5.7 mg, 45%).

LC-MS (m/z) 318.1 (M⁺); RT=2.33, (UV, ELSD) 93%, 100%.

The following compounds were prepared in an analogous fashion:

4b [4-(4-Isopropylbenzylamino)-2-methoxyphenyl]-carbamic acid ethylester

LC-MS (m/z) 341.3 (M⁺); RT=2.51, (UV, ELSD) 86%, 100%.

4c {2-Methoxy-4-[(3-methylthiophen-2-ylmethyl)-amino]-phenyl}-carbamicacid ethyl ester

LC-MS (m/z) 319.9 (M⁺); RT=2.10, (UV, ELSD) 79%, 99%.

4d [4-(2,4-Difluorobenzylamino)-2-methoxyphenyl]-carbamic acid ethylester

LC-MS (m/z) 337.2 ([M+H]⁺); RT=2.44, (UV, ELSD) 93%, 100%.

Example 5 5a [2-Cyclopentyloxy-4-(4-methoxybenzylamino)-phenyl]-carbamicacid ethyl ester

(2-Cyclopentyloxy-4-nitrophenyl)-carbamic acid ethyl (294 mg) wasdissolved in ethanol (26 mL). Zinc granules (1.63 g) and aqueoushydrochloric acid (5.0 mL, 2 M) were added. The resulting mixture wassonicated at room temperature for 6.5 hours, and then kept standing atroom temperature over night. Aqueous saturated sodium bicarbonate (100mL) was added, and the mixture was extracted with ethyl acetate (2×100mL). The organic phase was washed with water (100 mL) and brine (100mL), dried over magnesium sulfate, and evaporated in vacuo. Theresulting oil was dissolved in methanol (1.82 mL), and an aliquot (40μL) of this solution was mixed with a solution of 4-methoxybenzaldehyde(40 μL, 0.466 M in methanol). The resulting mixture was heated to 40° C.for 20 minutes. The solvent was evaporated in vacuo, and the remainingmaterial was dissolved in 1,2-dichloroethane (1 mL). Sodiumtriacetoxyborohydrate (20 mg) was added, and the resulting mixture waskept at room temperature for 2 hours, under 2 periods of sonication for10 minutes, respectively. The reaction mixture was filtered throughsilica gel (500 mg), and the column was washed with 1,2-dichloroethane(3 mL). The solvent was evaporated in vacuo yielding the title compound(6.0 mg, 84% from aldehyde).

LC-MS (m/z) 384.1 (M⁺); RT=2.40, (UV, ELSD) 76%, 96%.

The following compounds were prepared in an analogous fashion:

5b [2-Cyclopentyloxy-4-(3-fluoro-2-methylbenzylamino)-phenyl]-carbamicacid ethyl ester

The product was purified by preparative LC-MS.

LC-MS (m/z) 386.2 (M⁺); RT=3.22, (UV, ELSD) 80%, 91%.

5c [4-(3-Fluoro-2-methylbenzylamino)-2-phenethyloxyphenyl]-carbamic acidethyl ester

The product was purified by preparative LC-MS.

LC-MS (m/z) 422.3 (M⁺); RT=3.38, (UV, ELSD) 84%, 91%.

5d [2-Benzyloxy-4-(3-fluoro-2-methylbenzylamino)-phenyl]-carbamic acidethyl ester

The product was purified by preparative LC-MS.

LC-MS (m/z) 409.2 ([M+H]⁺); RT=3.30, (UV, ELSD) 80%, 89%.

5e [2-Benzyloxy-4-(4-methylsulfanylbenzylamino)-phenyl]-carbamic acidethyl ester

LC-MS (m/z) 422.1 (MN); RT=2.92, (UV, ELSD) 83%, 89%.

5f {4-[(Benzo[b]thiophen-3ylmethyl)-amino]-2-cyclopentyloxyphenyl}-carbamic acid ethyl ester

The product was purified by preparative LC-MS.

LC-MS (m/z) 411.1 ([M+H]⁺); RT=3.12, (UV, ELSD) 79%, 85%.

5g [4-(3-Fluoro-2-methylbenzylamino)-2-isopropoxyphenyl]-carbamic acidethyl ester

The product was purified by preparative LC-MS.

LC-MS (m/z) 361.2 ([M+H]⁺); RT=2.95, (UV, ELSD) 77%, 86%.

5h [2-Benzyloxy-4-(3-methoxybenzylamino)-phenyl]-carbamic acid ethylester

LC-MS (m/z) 407.3 ([M+H]⁺) RT=2.81, (UV, ELSD) 76%, 87%.

5i {4-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-2-isopropoxyphenyl}-carbamicacid ethyl ester

LC-MS (m/z) 372.1 (M⁺); RT=2.24, (UV, ELSD) 76%, 86%.

Example 6 6oN-{2-Chloro-4-[(N-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-cyclohexylpropionamide

Method A: To a mixture of2-Chloro-N(4)-(5-chloro-thiophen-2-ylmethyl)-N(4)-methyl-benzene-1,4-diamine(14 mg) and triethyl amine (0.04 mL) in acetonitrile (1 mL)3-cyclohexyl-proionyl chloride (0.03 mL) was added. Volatiles wereevaporated in vacuo and the title compound was separated by preparativeLC-MS.

Method B: To a stirred mixture of2-Chloro-N(4)-(5-chloro-thiophen-2-ylmethyl)-N(4)-methyl-benzene-1,4-diamine(470 mg, 1.64 mmol) and sodium bicarbonate in acetonitrile (40 mL)3-cyclohexyl-proionyl chloride (372 mg, 2.13 mmol) was added. After 1hour the reaction mixture was quenched with water (100 mL) and ice. Thetitle compound was separated by filtration as a grey-brown solid. Yield0.422 g, 60%. LC/MS (m/z) 425.4 ([M+H]⁺); RT=4.09, (UV, ELSD) 97%, 100%.¹H NMR (DMSO-d₆): 0.87 (m, 2H), 1.05-1.29 (m, 4H), 1.47 (q, 2H),1.56-1.76 (m, 5H), 2.29 (t, 2H), 2.91 (s, 3H), 4.67 (s, 2H), 6.76 (dd,1H), 6.83 (d, 1H), 6.88 (d, 1H), 6.96 (d, 1H), 7.27 (d, 1H).

The following compounds were prepared analogously by the method A fromcorresponding anilines and appropriate acid chlorides, chloroformiates,carbamyl chlorides, isocyanates, or di-tert-butyl dicarbonate (Boc₂O).Triethyl amine was used as a base in case of acid chlorides. Pyridinewas used as a base in case of chloroformiates and carbamyl chlorides. Nobase was used in case of isocyanates and Boc₂O. In case of(4-amino-3-chlorophenyl)-(5-chloro-thiophen-2-ylmethyl)-carbamic acidtert-butyl ester as an aniline, the residue after evaporation wastreated with 2% solution of anisol in a 1:1 mixture of trifluoroaceticacid and methylene chloride for 1 hour and evaporated again beforepreparative LC-MS:

6aN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-phenylacetamide

LC/MS (m/z) 406.2 ([M+2]⁺); RT=3.58, (UV, ELSD) 95.5%, 100.0%.

6bN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3,3-dimethylbutyramide

LC/MS (m/z) 384.1 (M⁺); RT=3.72, (UV, ELSD) 98.3%, 100.0%.

6cN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-phenylpropionamide

LC/MS (m/z) 418.1 (M⁺); RT=3.66, (UV, ELSD) 98.8%, 100.0%.

6dN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-butyramide

LC/MS (m/z) 356.1 (M⁺); RT=3.32, (UV, ELSD) 99.4%, 100.0%.

6e Pentanoic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide

LC/MS (m/z) 371.1 ([M+H]⁺); RT=3.55, (UV, ELSD) 98.3%, 100.0%.

6f Cyclopropanecarboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide

LC/MS (m/z) 355.0 ([M+H]⁺); RT=3.23, (UV, ELSD) 98.6%, 100.0%.

6g Cyclobutanecarboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide

LC/MS (m/z) 368.1 (M⁺); RT=3.46, (UV, ELSD) 93.4%, 98.5%.

6h Cyclopentanecarboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide

LC/MS (m/z) 382.0 (M⁺); RT=3.65, (UV, ELSD) 95.2%, 99.2%.

6i Cyclohexanecarboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide

LC/MS (m/z) 396.1 (M⁺); RT=3.83, (UV, ELSD) 97.3%, 99.8%.

6j N-{2-Chloro-4[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2thiophen-2-yl-acetamide

LC/MS (m/z) 412.0 ([M+2]⁺); RT=3.54, (UV, ELSD) 79.3%, 96.4%.

6kN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(3-methoxyphenyl)-acetamide

LC/MS (m/z) 435.0 ([M+H]⁺); RT=3.54, (UV, ELSD) 90.9%, 100.0%.

6lN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-chloro-phenyl)-acetamide

LC/MS (m/z) 438.0 (M⁺); RT=3.78, (UV, ELSD) 98.9%, 100.0%.

6mN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-methoxy-phenyl)-acetamide

LC/MS (m/z) 436.0 ([M+2]⁺); RT=3.53, (UV, ELSD) 92.0%, 99.4%.

6nN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-fluoro-phenyl)-acetamide

LC/MS (m/z) 421.9 (M⁺); RT=3.58, (UV, ELSD) 92.2%, 100.0%.

6pN-{2-Chloro-4[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2-dimethylpropionamide

LC/MS (m/z) 357.0 ([M+H]⁺); RT=3.34, (UV, ELSD) 96.4%, 99.5%.

6qN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-phenoxyacetamide

LC/MS (m/z) 406.9 ([M+H]⁺); RT=3.54, (UV, ELSD) 93.9%, 100.0%.

6rN-{2-Chloro-4[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-phenylacetamide

LC/MS (m/z) 391.1 ([M+H]⁺); RT=3.29, (UV, ELSD) 98.0%, 100.0%.

6sN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-3,3-dimethylbutyramide

LC/MS (m/z) 371.1 ([M+H]⁺); RT=3.40, (UV, ELSD) 94.1%, 98.1%.

6tN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-butyramide

LC/MS (m/z) 343.0 ([M+H]⁺); RT=3.01, (UV, ELSD) 77.8%, 88.9%.

6u Pentanoic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide

LC/MS (m/z) 357.1 ([M+H]; RT=3.24, (UV, ELSD) 95.7%, 100.0%.

6v Cyclopropanecarboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide

LC/MS (m/z) 340.8 (M⁺); RT 2.93, (UV, ELSD) 97.6%, 100.0%.

6w Cyclobutanecarboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide

LC/MS (m/z) 355.0 ([M+H]⁺); RT=3.15, (UV, ELSD) 95.1%, 100.0%.

6x Cyclopentanecarboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide

LC/MS (m/z) 368.8 ([M+H]⁺); RT=3.34, (UV, ELSD) 99.0%, 100.0%.

6y Cyclohexanecarboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide

LC/MS (m/z) 384.0 ([M+2]⁺); RT=3.50, (UV, ELSD) 98.2%, 100.0%.

6zN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-thiophen-2-yl-acetamide

LC/MS (m/z) 397.0 ([M+H]⁺); RT=3.24, (UV, ELSD) 94.8%, 100.0%.

6aaN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(3-methoxyphenyl)-acetamide

LC/MS (m/z) 420.9 ([M+H]⁺); RT=3.26, (UV, ELSD) 64.6%, 99.8%.

6abN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4-chlorophenyl)-acetamide

LC/MS (m/z) 425.0 ([M+H]⁺); RT=3.50, (UV, ELSD) 98.9%, 100.0%.

6ac N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4methoxyphenyl)-acetamide

LC/MS (m/z) 421.2 ([M+H]⁺); RT=3.24, (UV, ELSD) 95.3%, 99.6%.

6adN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4-fluorophenyl)-acetamide

LC/MS (m/z) 409.0 ([M+H]⁺); RT=3.31, (UV, ELSD) 97.2%, 100.0%.

6ae, 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide

LC/MS (m/z) 434.9 ([M+H]⁺); RT=3.21, (UV, ELSD) 92.7%, 100.0%.

6af 2,3-Dihydro-benzofuran-5-carboxylic acid{2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide

LC/MS (m/z) 419.3 ([M+H]⁺); RT=3.26, (UV, ELSD) 81.6%, 94.8%.

6agN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-3-cyclohexylpropionamide

LC/MS (m/z) 411.1 ([M+H]⁺); RT=3.89, (UV, ELSD) 95.3%, 99.5%.

6ahN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-2,2-dimethylpropionamide

LC/MS (m/z) 350.1 (M⁺); RT=2.98, (UV, ELSD) 91.8%, 99.1%.

6aiN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-2-phenylacetamide

LC/MS (m/z) 384.1 (M⁺); RT=3.04, (UV, ELSD) 95.8%, 100.0%.

6ajN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-3,3-dimethylbutyramide

LC/MS (m/z) 364.1 (M⁺); RT=3.10, (UV, ELSD) 93.0%, 99.7%.

6akN-{4-[(5-Chloro-thiophen-2-ylmethyl)-methyl)amino]-2-methyl-phenyl}-3-phenylpropionamide

LC/MS (m/z) 399.1 ([M+H]⁺); RT=3.12, (UV, ELSD) 98.2%, 99.9%.

6alN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-butyramide

LC/MS (m/z) 337.3 ([M+H]⁺); RT=2.68, (UV, ELSD) 92.5%, 99.7%.

6am2,2,2-Trichloro-N-{4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-acetamide

LC/MS (m/z) 411.9 ([M+H]⁺); RT=3.65, (UV, ELSD) 97.3%, 100.0%.

6an Cyclopropanecarboxylic acid{4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-amide

LC/MS (m/z) 335.1 ([M+H]⁺); RT=2.58, (UV, ELSD) 86.4%, 97.8%.

6ao Cyclobutanecarboxylic acid{4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide

LC/MS (m/z) 348.0 (M⁺); RT=2.79, (UV, ELSD) 95.4%, 100.0%.

6ap Cyclopentanecarboxylic acid{4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide

LC/MS (m/z) 363.2 ([M+H]⁺); RT=2.99, UV, ELSD) 97.7%, 99.9%.

6aq Cyclohexanecarboxylic acid{4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide

LC/MS (m/z) 377.1 ([M+H]⁺); RT=3.16, (UV, ELSD) 88.0%, 97.5%.

6arN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-thiophen-2-yl-acetamide

LC/MS (m/z) 390.0 (M⁺); RT=3.02, (UV, ELSD) 97.2%, 99.9%.

6asN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(3-methoxyphenyl)-acetamide

LC/MS (m/z) 416.0 ([M+2]⁺); RT=3.03, (UV, ELSD) 92.9%, 100.0%.

6atN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-malonamicacid methyl ester

LC/MS (m/z) 366.1 (M⁺); RT=2.53, (UV, ELSD) 94.5%, 100.0%.

6au2-(4-Chlorophenyl)-N-{4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-acetamide

LC/MS (m/z) 418.1 (M⁺); RT=3.31, (UV, ELSD) 97.3%, 99.9%.

6avN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(4-methoxyphenyl)-acetamide

LC/MS (m/z) 415.2 ([M+H]⁺); RT=2.99, (UV, ELSD) 87.8%, 98.1%.

6awN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(4-fluorophenyl)-acetamide

LC/MS (m/z) 403.2 ([M+H]⁺); RT=3.10, (UV, ELSD) 94.5%, 99.9%.

6axN-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-3-cyclohexylpropionamide

LC/MS (m/z) 405.1 ([M+H]⁺); RT=3.61, (UV, ELSD) 92.6%, 98.9%.

6ba{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid phenyl ester

LC/MS (m/z) 406.2 (M⁺); RT=3.78, (UV, ELSD) 96.3%, 99.4%.

6bb{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid benzyl ester

LC/MS (m/z) 422.1 ([M+2]⁺); RT=3.91, (UV, ELSD) 92.7%, 99.3%.

6bc{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid isobutyl ester

LC/MS (m/z) 388.1 ([M+2]⁺); RT=3.99, (UV, ELSD) 99.0%, 100.0%.

6bd{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid butyl ester

LC/MS (m/z) 386.0 (M⁺); RT=4.03, (UV, ELSD) 97.1%, 99.9%.

6be{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid hexyl ester

LC/MS (m/z) 415.9 ([M+2]⁺); RT=4.44, (UV, ELSD) 91.7%, 98.9%.

6bf{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid 4-nitrobenzyl ester

LC/MS (m/z) 465.0 (M⁺); RT=3.80, (UV, ELSD) 91.7%, 97.9%.

6bg{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid but-3-enyl ester

LC/MS (m/z) 383.9 (M⁺); RT=3.82, (UV, ELSD) 93.9%, 99.6%.

6bh{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid but-2-ynyl ester

LC/MS (m/z) 384.0 ([M+2]⁺); RT=3.61, (UV, ELSD) 76.3%, 99.0%.

6bi{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid 2,2-dimethylpropyl ester

LC/MS (m/z) 399.9 (M⁺); RT=4.11, (UV, ELSD) 98.8%, 99.6%.

6bj{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid 2-chlorobenzyl ester

LC/MS (m/z) 453.9 (M⁺); RT=4.12, (UV, ELSD) 97.5%, 99.8%.

6bk{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid 3-chloropropyl ester

LC/MS (m/z) 407.9 ([M+2]⁺); RT=3.72, (UV, ELSD) 88.7%, 97.5%.

6bl{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamicacid 2-benzyloxyethyl ester

LC/MS (m/z) 464.0 (M⁺); RT=3.86, (UV, ELSD) 89.1%, 98.7%.

6bm3-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-1-methyl-1-propyl-urea

LC/MS (m/z) 388.1 ([M+3]⁺); RT=3.38, (UV, ELSD) 86.0%, 99.5%.

6bo1-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-(2-fluorophenyl)-urea

LC/MS (m/z) 425.0 ([M+2]⁺); RT=3.65, (UV, ELSD) 94.9%, 99.9%.

Example 7 7aN-(4-{[5-(4-Chlorophenoxy)-1,3-dimethyl-1H-pyrazol-4-ylmethyl]-amino}-2-methylphenyl)-2,2-dimethylpropionamide

A mixture of N-(4-Amino-2-methylphenyl)-2,2-dimethylpropionamide (300mg, 1.45 mmol) and5-(4-Chlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (360 mg,1.45 mmol) in acetonitrile (4 mL) was heated and stirred at 170° C.under microwave irradiation for 20 minutes. The obtained reactionmixture was added carefully into solution of sodium cyanoborohydride(0.36 g) in methanol followed by acetic acid (1 mL). After 60 minutes itwas partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate solution and the organic layer was evaporated. The titlecompound was separated by flash chromatography on SiO₂ with gradientheptane-ethyl acetate and then precipitated from ethyl acetate withheptane. Yield 112 mg, 18%. LC/MS-TOF (m/z) 441; RT=2.34, (UV, ELSD)98%, 100%. ¹H NMR (DMSO-d₆): 1.18 (s, 9H), 1.96 (s, 3H), 2.15 (s, 3H),3.47 (s, 3H), 3.75 (d, 2H), 5.4 (t, 1H, NH), 6.29 (dd, 1H), 6.33 (d,1H), 6.24 (d, 1H), 6.99 (d, 2H), 7.41 (d, 2H), 8.58 (s, 1H, NH).

The following compounds were prepared analogously from correspondinganilines and aldehydes:

7b2,2-Dimethyl-N-{2-methyl-4-[(6-phenoxypyridin-3-ylmethyl)-amino]-phenyl}-propionamide

LC/MS-TOF (m/z) 390; RT=2.54, (UV, ELSD) 90%, 100%.

7c2,2-Dimethyl-N-{2-methyl-4-[(3-methyl-5-phenylisoxazol-4-ylmethyl)-amino]-phenyl}-propionamide

LC/MS-TOF (m/z) 378; RT=2.82, (UV, ELSD) 97%, 100%. ¹H NMR (DMSO-d₆):1.19 (s, 9H), 1.96 (s, 3H), 2.3 (s, 3H), 4.11 (d, 2H), 5.85 (t, 1H, NH),6.42 (overlapping m, 2H), 6.79 (d, 1H), 7.55 (m, 3H), 7.72 (d, 2H), 8.61(s, 1H, NH).

7d2-(4-Fluorophenyl)-N-{2-methyl-4[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-phenyl}-acetamide

LC/MS-TOF (m/z) 418.4 ([M+H]⁺); RT=2.75, (UV, ELSD) 99%, 100%. ¹H NMR(DMSO-d₆): 1.98 (s, 3H), 3.54 (s, 2H), 4.39 (d, 2H), 6.28 (t, 1H, NH),6.36 (dd, 1H), 6.43 (d, 1H), 6.91 (d, 1H), 7.14 (t, 2H), 7.35 (dd, 2H),7.85 (d, 1H), 7.99 (dd, 1H), 8.74 (d, 1H), 9.21 (s, 1H, NH).

7e3,3-Dimethyl-N-{2-methyl-4-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-phenyl}-butyramide

LC/MS-TOF (m/z) 380.5 ([M+H]⁺); RT=2.75, (UV, ELSD) 97%, 99%.

7f2-(4-Fluorophenyl)-N-{2-methyl-4-[(6-p-tolyloxypyridin-3-ylmethyl)-amino]-phenyl}-acetamide

LC/MS (m/z) 456.2 ([M+H]⁺); RT=2.79, (UV, ELSD) 82.5%, 99.8%

7g3,3-Dimethyl-N-{2-methyl-4-[(6-p-tolyloxypyridin-3-ylmethyl)-amino]-phenyl}-butyramide

LC/MS (m/z) 418.3 ([M+H]⁺); RT=2.75, (UV, ELSD) 62%, 93%

7hN-(4-{[6-(4-Cyanophenoxy)-pyrimidin-3-ylmethyl]-amino}-2-methylphenyl)-2-(4fluorophenyl)-acetamide

LC/MS (m/z) 467.2 ([M+H]⁺); RT=2.65, (UV, ELSD) 72%, 96%

7iN-{4-[(6-Chloropyridin-3-ylmethyl)-amino]-2-methylphenyl}-2-(4-fluorophenyl)-acetamide

LC/MS (m/z) 384.1 ([M+H]⁺); RT=2.46, (UV, ELSD) 87%, 99%

7j2-(4-Fluorophenyl)-N-{2-methyl-4-[(4-methyl-2-phenylpyrimidin-5-ylmethyl)-amino]-phenyl}-acetamide

LC/MS (m/z) 441.4 ([M+H]⁺); RT=2.97, (UV, ELSD) 90%, 100%

7k3,3-Dimethyl-N-{2-methyl-4-[(2-phenylpyrimidin-5-ylmethyl)-amino]-phenyl}-butyramide

LC/MS-TOF (m/z) 389.6 ([M+H]⁺); RT=2.83, (UV, ELSD) 89%, 95%

Example 8{4-[(5-Dimethylamino-3-methyl-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid propyl ester

A solution of (4-amino-2-methylphenyl)-carbamic acid propyl ester (21mg, 0.10 mmol) and5-dimethylamino-3-methyl-benzo[b]thiophene-2-carbaldehyde (26 mg, 0.12mmol) in acetonitrile (0.5 mL) was heated at 170° C. for 2 minutes usinga Personal Chemistry Smith Synthesizer microwave device. After coolingto room temperature, a solution of sodium cyanoborohydride (25 mg, 0.40mmol) in methanol (0.1 mL) was added followed by acetic acid (50 μL),and the mixture was stirred for 30 minutes. It was partitioned betweensaturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (10 mL),and the organic layer was dried over sodium sulfate and evaporated.Preparative LC-MS afforded the title compound (32 mg, 77% yield).

LC/MS-TOF (m/z) 412.4 ([M+H]⁺); RT=2.02, (UV, ELSD) 81%, 97%.

The following compounds were prepared analogously from appropriateanilines and aldehydes:

8b [4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2-methylphenyl]-carbamicacid ethyl ester

LC/MS (m/z) 371.2 ([M+H]⁺); RT=3.10, (UV, ELSD) 83%, 96%.

8c [4-(4-Chloro-benzylamino)-2-methylphenyl]-carbamic acid ethyl ester

LC/MS (m/z) 319.0 ([M+H]⁺); RT=2.57, (UV, ELSD) 79%, 95%.

3d{4-[(6-Methoxy-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid propyl ester

LC/MS-TOF (m/z) 384.4 (M⁺); RT=3.07, (UV, ELSD) 97%, 94%.

8e{4-[(7-Dimethylamino-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid propyl ester

LC/MS-TOF (m/z) 398.4 ([M+H]⁺); RT=2.64, (UV, ELSD) 97%, 100%.

8f{4-[(6-Methoxy-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamicacid ethyl ester

LC/MS-TOF (m/z) 370.4 (M⁺); RT=2.79, (UV, ELSD) 98%, 99%.

8g 4[(3-Methyl-4-propoxycarbonylamino-phenylamino)-methyl]-benzoic acidmethyl ester

LC/MS (m/z) 356.1 (Ma); RT=2.52, (UV, ELSD) 80%, 100%.

Example 9 9aN-[2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide

To a solution of(4-amino-3-methylphenyl)-(4-trifluoromethyl-benzyl)-carbamic acidtert-butyl ester (500 mg, 1.31 mmol) in dry tetrahydrofuran (10 mL) at0° C. was added pyridine (159 mL, 1.97 mmol) followed by butyrylchloride (164 μL, 1.58 mmol) dropwise. After 5 minutes, the reactionmixture was allowed to warm to room temperature, and stirring wascontinued for 1 hour. The reaction mixture was then diluted with ethylacetate, washed with 2 N HCl, saturated aqueous sodium bicarbonatetwice, and brine, and was then dried over magnesium sulfate. Solventswere evaporated in vacuo and the residue was dissolved in a 1:1 mixtureof dichloromethane and trifluoroacetic acid. After 30 minutes at roomtemperature the mixture was evaporated to dryness, the residue wasdissolved in ethyl acetate (10 mL), the solution was washed twice withsaturated aqueous sodium bicarbonate, twice with water, and was thendried over sodium sulfate. Evaporation of the solvents andrecrystallization of the residue from ethyl acetate:heptane gave thetitle compound as a colorless solid (226 mg, 49%).

¹H NMR (DMSO-d₆): 0.90 (t, 3H), 1.58 (sextet, 2H), 2.01 (s, 3H), 2.19(t, 2H), 4.35 (d, 2H), 6.24 (t, 1H), 6.32 (dd, 1H), 6.41 (d, 1H), 6.87(d, 1H), 7.55 (d, 2H), 7.67 (d, 2H), 8.91 (s, 1H). LC/MS (m/z) 350.2(M⁺); RT=2.77, (UV, ELSD) 95%, 100%.

The following compound was prepared analogously:

9b [2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acidethyl ester

Yield: 254 mg (55%).

LC/MS (m/z) 353.2 ([M+H]⁺); RT=2.93, (UV, ELSD) 97%, 100%.

¹H NMR (DMSO-d₆): 1.19 (br. s, 3H), 2.03 (s, 3H), 4.02 (q, 2H), 4.35 (s,2H), 6.29 (br. s, 1H), 6.33 (dd, 1H), 6.41 (d, 1H), 6.86 (br. d, 1H),7.55 (d, 2H), 7.67 (d, 2H), 8.39 (br. s, 1H).

Example 10 10aN-[2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-piperidin-1-yl-acetamide

To a solution of(4-amino-3-methylphenyl)-(4-trifluoromethyl-benzyl)-carbamic acidtert-butyl ester (15.2 mg, 40 mol) in DMF (100 μL) was added a solutionof O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 27.4 mg, 72 mol) in DMF (100 μL), followed byi-Pr₂NEt (25 μL, 144 mol) and piperidin-1-yl-acetic acid (8.6 mg, 60mol). The resulting mixture was shaken at room temperature for 3 hoursafter which it was diluted with ethyl acetate (10 mL), washed withsaturated aqueous ammonium chloride (2×10 mL), dried over sodiumsulfate, and evaporated. The residue was purified on a FlashMastersystem (silica, eluted with heptane/ethyl acetate mixtures) to yield[3-methyl-4-(2-piperidin-1-yl-acetylamino)-phenyl]-(4-trifluoromethylbenzyl)-carbamicacid tert-butyl ester as a white solid (10.7 mg, 53%). This wasdissolved in dichloromethane (200 μL) and trifluoroacetic acid (200 μL),and the solution was kept at room temperature for 30 minutes, afterwhich volatiles were evaporated and the residue was dried in vacuo at0.1 mmHg and +40° C. for 1 hour. The resulting trifluoroacetic acidaddition salt of the title compound was obtained as a yellow semisolidin quantitative yield.

LC/MS-TOF (m/z) 406.4 ([M+H]⁺); RT=2.02, (UV, ELSD) 99%, 98%.

The following compounds were prepared analogously from the appropriateanilines and carboxylic acids:

10bN-[2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-pyrrolidin-1-yl-acetamide

LC/MS-TOF (m/z) 392.3 ([M+H]⁺); RT=2.04, (UV, ELSD) 98%, 99%.

10cN-[2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-morpholin-4-yl-acetamide

LC/MS-TOF (m/z) 408.3 ([M+H]⁺); RT=1.98, (UV, ELSD) 99%, 100%.

10d (S)-2-Amino-4-methyl-pentanoic acid[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide

LC/MS-TOF (m/z) 394 ([M+H]⁺); RT=2.12, (UV, ELSD) 75%, 73%.

10e (R)-2-Amino-4-methyl-pentanoic acid[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide

LC/MS-TOF (m/z) 394 ([M+H]⁺); RT=2.29, (UV, ELSD) 89%, 100%.

10f 1-Amino-cyclopropanecarboxylic acid[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide

LC/MS-TOF (m/z) 365; RT=1.98, (UV, ELSD) 94%, 89%.

Example 11 Pentanoic acid{4[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide

To a solution ofN(4)-(5-Chloro-thiophen-2-ylmethyl)-2,N(4)-dimethyl-benzene-1,4-diamine(54 mg, 0.20 mmol) and triethylamine (84 μL, 0.60 mmol) in drytetrahydrofuran (1 mL) was added pentanoyl chloride (36 μL, 0.30 mmol),and the mixture was stirred for 1 hour at room temperature after whichit was partitioned between saturated aqueous sodium bicarbonate (5 mL)and ethyl acetate (5 mL). The organic layer was dried over sodiumsulfate, volatiles were evaporated, and the residue was purified on aFlashMaster system (silica, eluted with heptane/ethyl acetate mixtures)to yield the title compound as a white solid (61 mg, 86%).

LC/MS (m/z) 351.3 ([M+H]⁺); RT=3.06, (UV, ELSD) 100%, 99%.

Example 12 12a{2-Benzyloxy-4-[(4-fluorobenzyl)-(methyl)amino]-phenyl}-thiocarbamicacid S-ethyl ester

(3-Benzyloxy-4-nitrophenyl)(4-fluorobenzyl)methylamine (50 mg) wasdissolved in tetrahydrofuran (2 mL). Acetic acid (0.1 mL) and zincpowder (200 mg) were added and the resulting mixture was sonicated for 1hour. Additional zinc powder (100 mg) was added, and sonication wascontinued for 1 hour. The reaction mixture was filtered through silica(500 mg) and evaporated to dryness. 1,2-Dichloroethane (1 mL) was added,followed by diphosgene (0.03 mL). The reaction mixture was kept at roomtemperature for 15 minutes and then heated to 80° C. for 3 hours. Aftercooling to room temperature, triethylamine (0.12 mL) was added. Analiquot of the resulting mixture (one quarter) was mixed withthioethanol (0.026 mL), and the resulting mixture was shaken at roomtemperature over night. The mixture was evaporated to dryness, dissolvedin dimethylsulfoxide (0.2 mL) and subjected to preparative LC-MS toyield 7.6 mg of the title compound. Yield: 52%.

LC-MS (m/z) 425.2 ([M+H]⁺); RT 3.35, (UV, ELSD) 95%, 99%.

The following compounds were prepared analogously from the appropriatenitro compounds and nucleophiles:

12b{2-Cyclopentyloxy-4-[(4-fluorobenzyl)-(methyl)amino]-phenyl}-thiocarbamicacid S-ethyl ester

LC-MS (m/z) 403.1 ([M+H]⁺); RT=3.30, (UV, ELSD) 99%, 100%.

12c1-{2-Cyclopentyloxy-4-[(4-fluorobenzyl)-(methyl)amino]-phenyl}-3-ethyl-ureaEthylamine was used instead of thioethanol

LC-MS (m/z) 386.2 ([M+H]⁺); RT=2.08, (UV, ELSD) 97%, 100%.

Example 13 13aN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-chlorophenyl)-acetamide

2-Chloro-N(4)-(5-chloro-thiophen-2-ylmethyl)-N(4)-methyl-benzene-1,4-diamine(100 mg) was added to a solution of 4-chlorophenylacetyl chloride (69mg) in dry acetonitrile (2 mL) in a rubber-capped glass vial. Thereaction mixture was heated in a microwave device to 150° C. for 15minutes. The reaction mixture was poured into saturated aqueous sodiumbicarbonate (5 mL) and extracted with ethyl acetate (5 mL). The organicphase was washed with water (5 mL) and brine (5 mL), dried over sodiumsulfate, filtered, and evaporated to dryness. The crude product waspurified by flash chromatography (heptane/ethyl acetate, gradient) tofurnish 25.2 mg title compound. Yield: 16%.

LC-MS (m/z) 441.2 ([M+2]⁺); RT=3.83, (UV, ELSD) 91%, 99%.

The following compound was prepared analogously (2-phenylpropionic acidchloride was prepared by heating 2-phenylpropionic acid in thionylchloride and subsequent evaporation):

13bN-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-chlorophenyl)-propionamide

LC-MS (m/z) 453.0 (M⁺); RT=4.01, (UV, ELSD) 91%, 99%.

Example 14 14a4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-iodophenyl)-carbamic acidethyl ester

(4-Amino-2-iodophenyl)-carbamic acid ethyl ester (2.3 g) and5-chloro-thiophene-2-carbaldehyde (1.15 g) were dissolved in methanol (8mL) and heated in a sealed glass tube for 3 minutes to 130° C. undermicrowave irradiation. After cooling to room temperature, a solution ofsodium cyanoborohydride (4.7 g) in methanol (10 mL) was added, and theresulting mixture was again heated in a sealed glass tube for 5 minutesto 130° C. under microwave irradiation. After cooling to roomtemperature, the mixture was poured into water (50 mL) and extractedwith ethyl acetate (50 mL). The aqueous phase was extracted with ethylacetate (50 mL), and the combined organic phases were washed with water(2 times 80 mL) and brine (2 times 80 mL). The organic phase was driedover magnesium sulfate, filtered, and the solvent removed in vacuo. Theresulting oil was purified by flash chromatography (silica gel,heptane/ethyl acetate gradient). The resulting product was lyophillisedfrom dioxane/water to furnish the title compound (2 g, 63%) as orangesolid.

¹H NMR (CDCl₃): 1.31 (t, 3H), 4.02 (b, 1H), 4.21 (q, 2H), 4.35 (d, 2H),6.53 (b, 1H), 6.63 (dd, 1H), 6.75 (s, 2H), 7.06 (d, 1H), 7.63 (bs, 1H).

The following compound was prepared analogously:

14bN-{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-iodophenyl}-2-(4-fluorophenyl)-acetamide

¹H NMR (CDCl₃): 3.72 (s, 2H), 4.01 (b, 1H), 4.35 (d, 2H), 6.62 (dd, 1H),6.75 (s, 2H), 7.00 (d, 1H), 7.09-7.12 (m, 3H), 7.35 (dd, 2H), 7.85 (d,1H).

Example 15N-{5-[(5-Chloro-thiophen-2-ylmethyl)-amino]-4′-dimethylamino-biphenyl-2-yl}-2-(4-fluorophenyl)-acetamide

{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-iodophenyl}-carbamic acidethyl ester (270 mg), 4-dimethylaminophenylboronic acid (445 mg), andpalladium(II) acetate (ca. 10 mg) were suspended in acetone (5 mL).Potassium carbonate (0.54 mL, 5M aqueous solution) was added, and themixture was heated in a sealed glass tube in a microwave synthesizer for10 minutes at 125° C. After cooling to room temperature, the organicphase was separated, evaporated on silica gel, and subjected three timesto flash chromatography (heptane/ethyl acetate, gradient). The resultingsolid was recrystallised three times from acetonitrile to furnish 38 mgof the title compound as a colorless solid. The combined mother liquorswere evaporated on silica gel and subjected to flash chromatography. Theresulting product was recrystallised from methanol to furnish a secondcrop (12 mg) which was combined with the first crop to yield a total of50 mg (19%) of the title compound.

¹H NMR (DMSO-d₆): 2.91 (s, 6H), 3.44 (s, 2H), 4.39 (d, 2H), 6.32 (t,1H), 6.51 (dd, 2H), 6.61 (d, 2H), 6.93 (dd, 2H), 7.02-7.04 (m, 3H),7.07-7.10 (m, 2H), 7.22-7.23 (m, 2H), 9.01 (s, 1H).

LC-MS (m/z) 494.2 (M⁺); RT=2.50, (UV, ELSD) 95%, 99%.

Example 16 16a{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-quinolin-3-yl-phenyl}-carbamicacid ethyl ester

{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-iodophenyl}-carbamic acidethyl ester (15 mg), 3-quinolineboronic acid (29.7 mg), palladium(II)acetate (ca. 1 mg), potassium carbonate (0.035 mL, 5M aqueous solution),and acetone (2 mL) were mixed and heated in heated in a sealed glasstube in a microwave synthesizer for 10 minutes at 125° C. After coolingto room temperature, the reaction mixture was extracted with ethylacetate (4 mL), the organic phase washed with water (2×2 mL), and brine(2×2 mL), dried over magnesium sulfate, and filtered. The solvent wasremoved in vacuo, and the crude product was purified by preparativeLC-MS. The collected fraction was evaporated in: vacuo, redissolved inethyl acetate (5 mL), and the organic phase was washed with saturatedaqueous sodium bicarbonate (3 mL), water (3 mL), and brine (2×2 mL). Theorganic phase was dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo to furnish the title compound (5 mg, 33%).

LC-MS (m/z) 438.0 ([M+H]⁺); RT=2.32, (UV, ELSD) 89%, 100%.

The following compounds were prepared analogously:

16b{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-pyridin-3-yl-phenyl}-carbamicacid ethyl ester

LC-MS (m/z) 388.2 ([M+H]⁺); RT=2.01, (UV, ELSD) 97%, 100%.

16c{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-pyridin-4-yl-phenyl}-carbamicacid ethyl ester

LC-MS (m/z) 388.1 ([M+H]⁺); RT=1.95, (UV, ELSD) 98%, 100%.

16d{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-(6-methoxypyridin-3-yl)-phenyl}-carbamicacid ethyl ester

LC-MS (m/z) 418.3 ([M+H]⁺); RT=2.37, (UV, ELSD) 79%, 100%.

16e{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-quinolin-5-yl-phenyl}-carbamicacid ethyl ester

LC-MS (m/z) 438.0 ([M+H]⁺); RT=2.13, (UV, ELSD) 79%, 99%.

In Vitro and In Vivo Testing

The compounds of the invention have been tested and shown effect in oneor more of the below models:

Relative Efflux Through the KCNQ2 Channel.

This exemplifies a KCNQ2 screening protocol for evaluating compounds ofthe present invention. The assay measures the relative efflux throughthe KCNQ2 channel, and was carried out according to a method describedby Tang et al. (Tang, W. et. al., J. Biomol. Screen. 2001, 6, 325-331)for hERG potassium channels with the modifications described below.

An adequate number of CHO cells stably expressing voltage-gated KCNQ2channels were plated at a density sufficient to yield a mono-confluentlayer on the day of the experiment. Cells were seeded on the day beforethe experiment and loaded with 1 μCi/ml [⁸⁶Rb] over night. On the day ofthe experiment cells were washed with a HBSS-containing buffer. Cellswere pre-incubated with drug for 30 minutes and the ⁸⁶Rb⁺ efflux wasstimulated by a submaximal concentration of 15 mM KCl in the continuedpresence of drug for additional 30 minutes. After a suitable incubationperiod, the supernatant was removed and counted in a liquidscintillation counter (Tricarb). Cells were lysed with 2 mM NaOH and theamount of ⁸⁶Rb+ was counted. The relative efflux was calculated((CPM_(super)/(CPM_(super)+CPM_(cell)))_(Cmpd)/(CPM_(super)/(CPM_(super)+CPM_(cell)))_(15mM KCl))*100−100.

The compounds of the invention have an EC₅₀ of less than 20000 nM, inmost cases less than 200 nM and in many cases less than 200 nM.Accordingly, the compounds of the invention are considered to be usefulin the treatment of diseases associated with the KCNQ family potassiumchannels.

Electrophysiological Patch-Clamp Recordings.

Voltage-activated KCNQ2 currents were recorded from mammalian CHO cellsby use of conventional patch-clamp recordings techniques in thewhole-cell patch-clamp configuration (Hamill O P et. al. Pflügers Arch1981; 391: 85-100). CHO cells with stable expression ofvoltage-activated KCNQ2 channels were grown under normal cell cultureconditions in CO₂ incubators and used for electrophysiologicalrecordings 1-7 days after plating. KCNQ2 potassium channels wereactivated by voltage steps up to +80 mV in increments of 5-20 mV (orwith a ramp protocol) from a membrane holding potential between −100 mVand −40 mV (Tatulian L et al. J Neuroscience 2001; 21 (15): 5535-5545).The electrophysiological effects induced by the compounds were evaluatedon various parameters of the voltage-activated KCNQ2 current. Especiallyeffects on the activation threshold for the current and on the maximuminduced current were studied.

Some of the compounds of the invention have been tested in this test. Aleft-ward shift of the activation threshold or an increase in themaximum induced potassium current is expected to decrease the activityin neuronal networks and thus make the compounds useful in diseases withincreased neuronal activity—like epilepsia.

Maximum Electroshock

The test was conducted in groups of male mice using corneal electrodesand administering a square wave current of 26 mA for 0.4 seconds inorder to induce a convulsion characterised by a tonic hind limbextension (Wlaz et al. Epilepsy Research 1998, 30, 219-229).

Pilocarpine Induced Seizures

Pilocarpine induced seizures are induced by intraperitoneal injection ofpilocarpine 250 mg/kg to groups of male mice and observing for seizureactivity resulting in loss of posture within a period of 30 minutes(Starr et al. Pharmacology Biochemistry and Behavior 1993, 45, 321-325)

Electrical Seizure-Threshold Test

A modification of the up-and-down method (Kimball et a., RadiationResearch 1957, 1-12) was used to determine the median threshold toinduce tonic hind-limb extension in response to corneal electroshock ingroups of male mice. The first mouse of each group received anelectroshock at 14 mA, (0.4 s, 50 Hz) and was observed for seizureactivity. If a seizure was observed the current was reduced by 1 mA forthe next mouse, however, if no seizure was observed then the current wasincreased by 1 mA. This procedure was repeated for all 15 mice in thetreatment group.

Chemical Seizure-Threshold Test

The threshold dose of pentylenetetrazole required to induce a clonicconvulsion was measured by timed infusion of pentylenetetrazole (5 mg/mlat 0.5 ml/minute) into a lateral tail vein of groups of male mice (Nuttet al. J Pharmacy and Pharmacology 1986, 38, 697-698).

Amygdala Kindling

Rats underwent surgery to implantation of tri-polar electrodes into thedorsolateral amygdala. After surgery the animals were allowed to recoverbefore the groups of rats received either varying doses of test compoundor the drug's vehicle. The animals were stimulated with their initialafter discharge threshold+25 μA daily for 3-5 weeks and on each occasionseizure severity, seizure duration, and duration of electrical afterdischarge were noted. (Racine. Electroencephalography and ClinicalNeurophysiology 1972, 32, 281-294).

Side Effects

Central nervous system side effects were measured by measuring the timemice would remain on rotarod apparatus (Capacio et al. Drug and ChemicalToxicology 1992, 15, 177-201); or by measuring their locomotor activityby counting the number of infra-red beams crossed in a test cage((Watson et al. Neuropharmacology 1997, 36, 1369-1375). Hypothermicactions on the animals core body temperature of the compound weremeasured by either rectal probe or implanted radiotelemetry transmitterscapable of measuring temperature (Keeney et al. Physiology and Behaviour2001, 74, 177-184.

Pharmacokinetics

The pharmacokinetic properties of the compounds were determined via.i.v. and p.o. dosing to Spraque Dawley rats, and, thereafter, drawingblood samples over 20 hours. Plasma concentrations were determined withLC/MS/MS.

1. A substituted p-diaminobenzene derivative of the general formula I

wherein: s is 0 or 1; U is O, S, SO₂, SONR¹¹, or CONR¹¹; wherein: R¹¹ ishydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, orC₃₋₈-cycloalk(en)yl-C₁₋₆ -alk(en/yn)yl; or R² and R¹¹ taken togetherwith the nitrogen atom form a 5-8 membered saturated or unsaturatedring, which optionally contains 1, 2 or 3 further heteroatoms; q is 0 or1; X is CO or SO₂; with the proviso that q is 0 when X is SO₂; Z is O orS; R¹ is hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆ -alk(en/yn)yl, acyl, hydroxy-C₁₋₆-alk(en/yn)yl,hydroxy-C₃₋₈-cycloalk(en)yl, hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₃₋₈-cycloalk(en)yl, halo -C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en) yl or cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; R² is hydrogen, C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆ -alk(en/yn)yl, Ar,Ar—C₁₋₆-alk(en/yn)yl, Ar—C₃₋₈-cycloalk(en)yl,Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, acyl,hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk (en)yl, hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, halogen, halo-C₁₋₆-alk(en/yn)yl,halo-C₃₋₈-cycloalk (en)yl, halo -C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,cyano, cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈cycloalk(en)yl,cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,NR¹⁰R^(10′)—C₁₋₆-alk(en/yn)yl, NR¹⁰R^(10′)—C₃₋₈ -cycloalk(en)yl orNR¹⁰R^(10′)—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; wherein: R¹⁰ andR^(10′) are each independently hydrogen, C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk(en)yl,hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₃₋₈-cycloalk(en)yl, halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl orcyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; or R¹⁰ and R^(10′) takentogether with the nitrogen atom form a 5-8 membered saturated orunsaturated ring, which optionally contains 1, 2 or 3 furtherheteroatoms; with the proviso that: when R² is halogen or cyano, then sis 0; and when s is 1 and R² is a hydrogen atom or acyl, then U is O orS; R³ is C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, heterocycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,heterocycloalk(en)yl-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yloxy-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-C₃₋₈-cycloalk(en)yl,C₁₋₆-alk(en/yn)yloxy-heterocycloalk(en)yl,C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy -carbonyl-C₁₋₆-alk(en/yn)yl,hydroxy-C₁₋₆-alk(en/yn)yl, hydroxy-C₃₋₈-cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,hydroxy-C₁₋₆-alk(en/yn)yl -C₃₋₈-cycloalk(en)yl,hydroxy-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, halo-C₃₋₈-cycloalk(en)yl, halo-heterocycloalk(en)yl,halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,halo-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, cyano-C₁₋₆-alk(en/yn)yl,cyano-C₃₋₈-cycloalk(en)yl, cyano-heterocycloalk(en)yl,cyano-C₃₋₈-cycloalk(en)yl -C₁₋₆-alk(en/yn)yl,cyano-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl, cyano-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, acyl-C₁₋₆-alk(en/yn)yl, acyl-C₃₋₈-cycloalk(en)yl,acyl-heterocycloalk(en)yl, acyl-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,acyl-C₁₋₆-alk(en/yn)yl-C₃₋₈-cycloalk(en)yl,acyl-C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl, NR¹²R^(12′), optionallysubstituted NR¹²R^(12′)-C₁₋₆-alk(en/yn)yl, optionally substitutedNR¹²R^(12′)-C₃₋₈-alk(en/yn)yl, or optionally substitutedNR¹²R^(12′)-C₃₋₈-alk(en/yn)yl-C₁₋₆-alk(en/yn)yl; wherein: R¹² andR^(12′) are each independently hydrogen, C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar,Ar—C₁₋₆-alk(en/yn)yl, Ar—C₃₋₈-cycloalk(en)yl,Ar—C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar-heterocycloalk(en)yl,Ar-oxy-C₁₋₆-alk(en/yn)yl, Ar-oxy-C₃₋₈-cycloalk(en)yl,Ar-oxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar-oxy-heterocycloalk(en)yl, hydroxy-C₁₋₆-alk(en/yn)yl,hydroxy-C₃₋₈-cycloalk(en)yl,hydroxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₃₋₈-cycloalk(en)yl, halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk(en)yl, or cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; or R¹² and R^(12′) takentogether with the nitrogen atom form a 5-8 membered saturated orunsaturated ring, which optionally contains 1, 2 or 3 furtherheteroatoms; with the proviso that when R³ is NR¹²R^(12′) then q is 0;and Y is a group of formula XXXXI:

wherein: “|” represents a bond attaching the group represented by Y tothe carbon atom; V is C or CH; and k is 0, 1, 2 or 3; and each R⁵ isindependently C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk (en)yl, C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl, Ar—C₃₋₈-cycloalk(en)yl,Ar—C₃₋₈-cycloalk (en)yl-C₁₋₆-alk(en/yn)yl , Ar-oxy,Ar-oxy-C₁₋₆alk(en/yn)yl, Ar-oxy-C₃₋₈-cycloalk(en)yl, C₁₋₆-alk (en/yn)yl-heterocycloalk(en)yl, Ar-oxy-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl,acyl, C₁₋₆-alk (en/yn)yloxy, C₃₋₈-cycloalk(en)yloxy,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yloxy, C₁₋₆-alk(en/yn)yloxy-carbonyl,halogen, halo-C₁₋₆-alk(en/yn)yl, halo-C₃₋₈-cycloalk(en)yl,halo-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, —CO—NR⁶R^(6′), cyano,cyano-C₁₋₆-alk(en/yn)yl, cyano-C₃₋₈-cycloalk (en)yl,cyano-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, NR⁷R^(7′), S—R⁸ or SO₂R⁸;or two adjacent R⁵ groups taken together with the aromatic group form a5-8 membered ring, which optionally contains one or two heteroatoms;wherein: R⁶ and R^(6′) are each independently hydrogen,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl or Ar; R⁷ and R^(7′) are eachindependently hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar, heterocycloalk(en)yl-C₁₋₆-alk(en/yn)yl, heterocycloalk(en)yl-C₃₋₈-cycloalk(en)yl,heterocycloalk(en)yl-C₃₋₈-cycloalk(en)yl-C₁₋₆-alk (en/yn)yl,heterocycloalk(en)yl-Ar or acyl; or R⁷ and R^(7′) taken together withthe nitrogen atom form a 5-8 membered saturated or unsaturated ringwhich optionally contains 1, 2 or 3 further heteroatoms; and R⁸ ishydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, Ar or —NR⁹R^(9′); wherein: R⁹ andR^(9′) are each independently hydrogen, C₁₋₆-alk(en/yn)yl,C₃₋₈-cycloalk(en)yl or C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl; or saltsthereof.
 2. The compound according to claim 1, wherein R¹ isC₁₋₆-alk(en/yn)yl or a hydrogen atom.
 3. The compound according to claim1, wherein s is
 0. 4. The compound according to claim 1, wherein s is 1.5. The compound according to claim 4, wherein U is an oxygen atom. 6.The compound according to claim 1, wherein R² is hydrogen,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,halogen, halo-C₁₋₆-alk(en/yn)yl or cyano; with the provisos that when R²is halogen or cyano, then s is 0; and when s is 1 and R² is a hydrogenatom, then U is O or S.
 7. The compound according to claim 1, wherein Zis an oxygen atom.
 8. The compound according to claim 1, wherein Z is asulfur atom.
 9. The compound according to claim 1, wherein q is
 0. 10.The compound according to claim 1, wherein q is
 1. 11. The compoundaccording to claim 1, wherein X is CO.
 12. The compound according toclaim 1, wherein R³ is C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, heterocycloalk (en)yl-C₁₋₆-alk(en/yn)yl, heterocycloalk(en)yl, Ar, Ar—C₁₋₆-alk(en/yn)yl,Ar-oxy-C₁₋₆-alk (en/yn)yl, Ar—C₁₋₆-alk(en/yn)yloxy-C₁₋₆-alk(en/yn)yl,C₁₋₆-alk(en/yn)yloxy-carbonyl-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl, NR¹²R^(12′), optionally substitutedNR¹²R^(12′)—C₁₋₆-alk(en/yn)yl, or optionally substitutedNR¹²R^(12′)—C₃₋₈-cycloalk(en)yl.
 13. The compound according to claim 12,wherein R¹² and R^(12′) are each independently hydrogen,C₁₋₆-alk(en/yn)yl or Ar.
 14. The compound according to claim 1, whereinV is CH.
 15. The compound according to claim 1, wherein each R⁵ isindependently C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)yl-heterocycloalk(en)yl,Ar, C₁₋₆-alk(en/yn)yloxy, Ar-oxy, C₁₋₆-alk(en/yn)yloxy-carbonyl,halogen, halo-C₁₋₆-alk(en/yn)yl, NR⁷R^(7′), S—R⁸ or SO₂R⁸; or twoadjacent R⁵ groups taken together with the aromatic group form a 5-8membered ring, which optionally contains one or two heteroatoms.
 16. Thecompound according to claim 15, wherein both R⁷ and R^(7′) areC₁₋₆-alk(en/yn)yl.
 17. The compound according to claim 15, wherein R⁸ isC₁₋₆-alk(en/yn)yl or Ar.
 18. The compound according to claim 1, whereinthe compound is:2-(4-Fluorophenyl)-N-{2-methyl-4-[(6-p-tolyloxypyridin-3-ylmethyl)-amino]-phenyl}-acetamide;2-(4-Fluorophenyl)-N-{2-methyl-4-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-phenyl}-acetamide;3,3-Dimethyl-N-{2-methyl-4-[(6-p-tolyloxypyridin-3-ylmethyl)-amino]-phenyl}-butyramide;3,3-Dimethyl-N-{2-methyl-4-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-phenyl}-butyramide;N-(4-{[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]-amino}-2-methylphenyl)-2-(4-fluorophenyl)-acetamide;N-{4-[(6-Chloropyridin-3-ylmethyl)-amino]-2-methylphenyl}-2-(4-fluorophenyl)-acetamide;or2,2-Dimethyl-N-{2-methyl-4-[(6-phenoxypyridin-3-ylmethyl)-amino]-phenyl}-proprionamide; or a salt thereof.
 19. A pharmaceutical compositioncomprising one or more pharmaceutically acceptable carriers or diluentsand a compound according to claim 1.